Patent application title: Human Potassium Channel Genes
Inventors:
Andrew P. Miller (San Mateo, CA, US)
Ping Hu (Bethesda, MD, US)
Mark Edward Curran (Raleigh, NC, US)
Marc Rutter (San Diego, CA, US)
Jian-Ying Wang (San Diego, CA, US)
Assignees:
ICAGEN, INC.
IPC8 Class:
USPC Class:
435325
Class name: Chemistry: molecular biology and microbiology animal cell, per se (e.g., cell lines, etc.); composition thereof; process of propagating, maintaining or preserving an animal cell or composition thereof; process of isolating or separating an animal cell or composition thereof; process of preparing a composition containing an animal cell; culture media therefore
Publication date: 2010-10-28
Patent application number: 20100273256
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Patent application title: Human Potassium Channel Genes
Inventors:
ANDREW P. MILLER
PING HU
MARK EDWARD CURRAN
MARC RUTTER
JIAN-YING WANG
Agents:
Annette S. Parent, Esq.;Townsend and Townsend and Crew LLP
Assignees:
Origin: SAN FRANCISCO, CA US
IPC8 Class:
USPC Class:
Publication date: 10/28/2010
Patent application number: 20100273256
Abstract:
Methods for isolating K+Hnov genes are provided. The K+Hnov nucleic acid
compositions find use in identifying homologous or related proteins and
the DNA sequences encoding such proteins; in producing compositions that
modulate the expression or function of the protein; and in studying
associated physiological pathways. In addition, modulation of the gene
activity in vivo is used for prophylactic and therapeutic purposes, such
as identification of cell type based on expression, and the like.Claims:
1-14. (canceled)
15. An isolated nucleic acid encoding a polypeptide comprising a subunit of a potassium channel, the nucleic acid comprising a nucleotide sequence of SEQ ID NO:17.
16. The isolated nucleic acid of claim 15, wherein the nucleic acid encodes a polypeptide comprising an alpha subunit of a homomeric potassium channel.
17. An expression vector encoding the nucleic acid of claim 15.
18. A host cell transfected with the expression vector of claim 17.
19. An isolated nucleic acid encoding a polypeptide comprising a subunit of a potassium channel, the nucleic acid hybridizing under stringent conditions, wherein the hybridization reaction is incubated at 50.degree. C. or above in a solution comprising 0.1.times.SSC and washed at 55.degree. C. in a solution comprising 1.times.SSC, to the complement of a nucleotide sequence of SEQ ID NO:9.
20. An isolated nucleic acid encoding a polypeptide comprising a subunit of a potassium channel, the polypeptide comprising an amino acid sequence of SEQ ID NO:18.
Description:
INTRODUCTION
Background
[0001]Ion channels are multi-subunit, membrane bound proteins critical for maintenance of cellular homeostasis in nearly all cell types. Channels are involved in a myriad of processes including modulation of action potentials, regulation of cardiac myocyte excitability, heart rate, vascular tone, neuronal signaling, activation and proliferation of T-cells, and insulin secretion from pancreatic islet cells. In humans, ion channels comprise extended gene families with hundreds, or perhaps thousands, of both closely related and highly divergent family members. The majority of known channels regulate the passage of sodium (Na+), chloride (Cl+), calcium (Ca++) and potassium (K+) ions across the cellular membrane.
[0002]Given their importance in maintaining normal cellular physiology, it is not surprising that ion channels have been shown to play a role in heritable human disease. Indeed, ion channel defects are involved in predisposition to epilepsy, cardiac arrhythmia (long QT syndrome), hypertension (Bartter's syndrome), cystic fibrosis, (defects in the CFTR chloride channel), several skeletal muscle disorders (hyperkalemic periodic paralysis, paramyotonia congenita, episodic ataxia) and congenital neural deafness (Jervell-Lange-Nielson syndrome), amongst others.
[0003]The potassium channel gene family is believed to be the largest and most diverse ion channel family. K+ channels have critical roles in multiple cell types and pathways, and are the focus of significant investigation. Four human conditions, episodic ataxia with myokymia, long QT syndrome, epilepsy and Bartter's syndrome have been shown to be caused by defective K+ ion channels. As the K+ channel family is very diverse, and given that these proteins are critical components of virtually all cells, it is likely that abnormal K+ channels will be involved in the etiology of additional renal, cardiovascular and central nervous system disorders of interest to the medical and pharmaceutical community.
[0004]The K+ channel superfamily can be broadly classified into groups, based upon the number of transmembrane domain (TMD) segments in the mature protein. The minK (IsK) gene contains a single TMD, and although not a channel by itself, minK associates with different K+ channel subunits, such as KvLQT1 and HERG to modify the activity of these channels. The inward rectifying K+ channels (GIRK, IRK, CIR, ROMK) contain 2 TMD domains and a highly conserved pore domain. Twik-1 is a member of the newly emerging 4TMD K+ channel subset. Twik-like channels (leak channels) are involved in maintaining the steady-state K+ potentials across membranes and therefore the resting potential of the cell near the equilibrium potential for potassium (Duprat et al. (1997) EMBO J 16(17):5464-5471). These proteins are particularly intriguing targets for therapeutic regulation. The 6TMD, or Shaker-like channels, presently comprise the largest subset of known K+ channels. The slopoke (slo) related channels, or Ca++ regulated channels apparently have either 10 TMD, or 6 TMD with 4 additional hydrophobic domains.
[0005]Four transmembrane domain, tandem pore domain K+ channels (4T/2P channels) represent a new family of potassium selective ion channels involved in the control of background membrane conductances. In mammals, five channels fitting the 4T/2P architecture have been described: TWIK, TREK, TASK-1, TASK-2 and TRAAK. The 4T/2P channels all have distinct characteristics, but are all thought to be involved in maintaining the steady-state K+ potentials across membranes and therefore the resting potential of the cell near the equilibrium potential for potassium (Duprat et al. (1997) EMBO J 16(17):5464-5471). These proteins are particularly intriguing targets for therapeutic regulation. Within this group, TWIK-1, TREK-1 and TASK-1 and TASK-2 are widely distributed in many different tissues, while TRAAK is present exclusively in brain, spinal cord and retina. The 4T/2P channels have different physiologic properties; TREK-1 channels, are outwardly rectifying (Fink et al. (1996) EMBO J 15(24):6854-62), while TWIK-1 channels, are inwardly rectifying (Lesage et al. (1996) EMBO J 15(5):1004-11. TASK channels are regulated by changes in PH while TRAAK channels are stimulated by arachidonic acid (Reyes et al. (1998) JBC 273(47):30863-30869).
[0006]The degree of sequence homology between different K+ channel genes is substantial. At the amino acid level, there is about 40% similarity between different human genes, with distinct regions having higher homology, specifically the pore domain. It has been estimated that the K+ channel gene family contains approximately 102-103 individual genes. Despite the large number of potential genes, an analysis of public sequence databases and the scientific literature demonstrates that only a small number, approximately 20-30, have been identified. This analysis suggests that many of these important genes remain to be identified.
[0007]Potassium channels are involved in multiple different processes and are important regulators of homeostasis in nearly all cell types. Their relevance to basic cellular physiology and role in many human diseases suggests that pharmacological agents could be designed to specific channel subtypes and these compounds then applied to a large market (Bulman, D. E. (1997) Hum Mol Genet 6:1679-1685; Ackerman, M. J. and Clapham D. E. (1997) NEJM 336:1575-1586, Curran, M. E. (1998) Current Opinion in Biotechnology 9:565-572). The variety of therapeutic agents that modulate K+ channel activity reflects the diversity of physiological roles and importance of K+ channels in cellular function. A difficulty encountered in therapeutic use of therapeutic agents that modify K+ channel activity is that the presently available compounds tend to be non-specific and elicit both positive and negative responses, thereby reducing clinical efficacy. To facilitate development of specific compounds it is desirable to have further characterize novel K+ channels for use in in vitro and in vivo assays.
Relevant Literature
[0008]A large body of literature exists in the general area of potassium channels. A review of the literature may be found in the series of books, "The Ion Channel Factsbook", volumes 1-4, by Edward C. Conley and William J. Brammar, Academic Press. An overview is provided of: extracellular ligand-gated ion channels (ISBN: 0121844501), intracellular ligand-gated channels (ISBN: 012184451X), Inward rectifier and intercellular channels (ISBN: 0121844528), and voltage gated channels (ISBN: 0121844536). Hille, B. (1992) "Ionic Channels of Excitable Membranes", 2nd Ed. Sunderland MA: Sinauer Associates, also reviews potassium channels.
[0009]Jan and Jan (1997) Annu. Rev. Neurosci. 20:91-123 review cloned potassium channels from eukaryotes and prokaryotes. Ackerman and Clapham (1997) N. Engl. J. Med. 336:1575-1586 discuss the basic science of ion channels in connection with clinical disease. Bulman (1997) Hum. Mol. Genet. 6:1679-1685 describe some phenotypic variation in ion channel disorders.
[0010]Stephan et al. (1994) Neurology 44:1915-1920 describe a pedigree segregating a myotonia with muscular hypertrophy and hyperirritability as an autosomal dominant trait (rippling muscle disease, Ricker et al. (1989) Arch. Neurol. 46405-408). Electromyography demonstrated that mechanical stimulation provoked electrically silent contractions. The responsible gene was localized to the distal end of the long arm of chromosome 1, in a 12-cM region near D1S235.
[0011]Type II pseudohypoaldosteronism is the designation used for a syndrome of chronic mineralocorticoid-resistant hyperkalemia with hypertension. The primary abnormality in type II PHA is thought to be a specific defect of the renal secretory mechanism for potassium, which limits the kaliuretic response to, but not the sodium and chloride reabsorptive effect of, mineralocorticoid. By analysis of linkage in families with autosomal dominant transmission, Mansfield et al. (1997) Nature Genet. 16:202-205 demonstrated locus heterogeneity of the trait, with linkage of the PHA2 gene to 1q31-q42 and 17p11-q21.
[0012]Sequences of four transmembrane, two pore potassium channels have been previously described. Reyes et al. (1998) J Biol Chem 273(47):30863-30869 discloses a pH sensitive channel. As with the related TASK-1 and TRAAK channels, the outward rectification is lost at high external K+ concentration. The TRAAK channel is described by Fink et al. (1998) EMBO J 17(12):3297-308. A cardiac two-pore channel is described in Kim et al. (1998) Circ Res 82(4):513-8. An open rectifier potassium channel with two pore domains in tandem and having a postsynaptic density protein binding sequence at the C terminal was cloned by Leonoudakis et al. (1998) J Neurosci 18(3):868-77.
[0013]The electrophysiological properties of Task channels are of interest, (Duprat et al. (1997) EMBO J 16:5464-71). TASK currents are K+-selective, instantaneous and non-inactivating. They show an outward rectification when external [K+] is low, which is not observed for high [K+]out, suggesting a lack of intrinsic voltage sensitivity. The absence of activation and inactivation kinetics as well as voltage independence are characteristic of conductances referred to as leak or background conductances. TASK is very sensitive to variations of extracellular pH in a narrow physiological range, a property probably essential for its physiological function, and suggests that small pH variations may serve a communication role in the nervous system.
SUMMARY OF THE INVENTION
[0014]Isolated nucleotide compositions and sequences are provided for K+Hnov genes. The K+Hnov nucleic acid compositions find use in identifying homologous or related genes; in producing compositions that modulate the expression or function of its encoded proteins; for gene therapy; mapping functional regions of the proteins; and in studying associated physiological pathways. In addition, modulation of the gene activity in vivo is used for prophylactic and therapeutic purposes, such as treatment of potassium channel defects, identification of cell type based on expression, and the like.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
[0015]Nucleic acid compositions encoding K+Hnov polypeptides are provided. They are used in identifying homologous or related genes; in producing compositions that modulate the expression or function of the encoded proteins; for gene therapy; mapping functional regions of the proteins; and in studying associated physiological pathways. The K+Hnov gene products are members of the potassium channel gene family, and have high degrees of homology to known potassium channels. The encoded polypeptides may be alpha subunits, which form the functional channel, or accessory subunits that act to modulate the channel activity.
Characterization of K+Hnov
[0016]The sequence data predict that the provided K+Hnov genes encode potassium channels. Table 1 summarizes the DNA sequences, corresponding SEQ ID NOs, chromosomal locations, and polymorphisms. The provided sequences may encode a predicted K+channel, e.g. voltage gated, inward rectifier, etc.; or a modulatory subunit.
[0017]Electrophysiologic characterization of ion channels is an important part of understanding channel function. Full length ion channel cDNAs may be combined with proper vectors to form expression constructs of each individual channel. Functional analyses of expressed channels can be performed in heterologous systems, or by expression in mammalian cell lines. For expression analyses in heterologous systems such as Xenopus oocytes, synthetic mRNA is made through in vitro transcription of each channel construct. mRNA is then injected, singly or in combination with interacting channel subunit mRNAs, into prepared oocytes and the cells allowed to express the channel for several days. Oocytes expressing the channel of interest are then analyzed by whole cell voltage clamp and patch clamp techniques.
[0018]To determine the properties of each channel when expressed in mammalian cells expression vectors specific to this type of analyses may be constructed and the resultant construct used to transform the target cells (for example human embryonic kidney (HEK) cells). Both stable and transiently expressing lines may be studied using whole cell voltage clamp and patch clamp techniques. Data obtained from EP studies includes, but is not limited to: current profiles elicited by depolarization and hyperpolarization, current-voltage (I-V) relationships, voltage dependence of activation, biophysical kinetics of channel activation, deactivation, and inactivation, reversal potential, ion selectivity, gating properties and sensitivity to channel antagonists and agonists.
[0019]Heterologous or mammalian cell lines expressing the novel channels can be used to characterize small molecules and drugs which interact with the channel. The same experiments can be used to assay for novel compounds which interact with the expressed channels.
[0020]In many cases the functional ion channel formed by K+Hnov polypeptides will be heteromultimers. Heteromultimers are known to form between different voltage gated, outward rectifying potassium channel α subunits, generally comprising four subunits, and frequently associated with auxiliary, β subunits. Typically such α subunits share a six-transmembrane domain structure (S1-S6), with one highly positively charged domain (S4) and a pore region situated between S5 and S6. Examples of such subunits are K+Hnov4, K+Hnov9, and K+Hnov12. Channels are also formed by mutimerization of subunits of the two transmembrane and one pore architecture. It is predicted that two subunits of K+Hnov49 or K+Hnov59 will be required to form a functional channel.
[0021]Heteromultimers of greatest interest are those that form between subunits expressed in the same tissues, and are a combination of subunits from the same species. In addition, the formation of multimers between the subject polypeptides and subunits that form functional channels are of particular interest. The resulting channel may have decreased or increased conductance relative to a homomultimer, and may be altered in response to beta subunits or other modulatory molecules.
[0022]Known voltage gated K+ channel α subunits include Kv1.1-1.8 (Gutman et al. (1993) Sem. Neurosci. 5:101-106); Kv2.1-2.2; Kv3.1-3.4; Kv4.1-4.3; Kv5.1; Kv6.1; Kv7:1; Kv8.1; Kv9.1-9.2. The subunits capable of forming ion inducing channels include all of those in the Kv1 through Kv4; and Kv7 families. The Kv5.1, Kv6.1, Kv8.1 and Kv9.1-9.2 subunits may be electrically silent, but functional in modifying the properties in heteromultimers.
TABLE-US-00001 TABLE 1 Chromosome Name cDNA SEQ Protein SEQ Polymorphisms Position Channel Type K+Hnov1 SEQ ID NO: 1 SEQ ID NO: 2 Alternative poly(A) tail: 1236, 2q37 ATP-sensitive inward rectifying 2395 K+Hnov4 SEQ ID NO: 3 SEQ ID NO: 4 A312C unknown Voltage gated K+ channel T335C A377G T344C A401G CA410-411GG (Ala/Thr) K+Hnov6 SEQ ID NO: 5 SEQ ID NO: 6 2p23 Delayed rectifying K+ channel K+Hnov9 SEQ ID NO: 7 SEQ ID NO: 8 Alternative poly(A) tail: 2304 8q23 Voltage gated K+ channel K+Hnov12 SEQ ID NO: 9 SEQ ID NO: 10 C321T (Pro/Leu) Xp21 Voltage gated K+ channel A375G (Glu/Gly) C407T (Leu/Phe) K+Hnov15 SEQ ID NO: 11 SEQ ID NO: 12 Alternative poly(A) tail: 1427 13q14 modulatory subunit A689G (Gly/Arg) K+Hnov27 SEQ ID NO: 13 SEQ ID NO: 14 T365A (Ile/Asn) 18q12 modulatory subunit K+Hnov2 SEQ ID NO: 15 SEQ ID NO: 16 N/A N/A 4 transmembrane domain, 2 pore domain K+ channel K+Hnov 11 SEQ ID NO: 17 SEQ ID NO: 18 N/A N/A Human ortholog of murine gene, 6 transmembrane dominas, voltage gated, delayed rectifier K+ channel K+Hnov 14 SEQ ID NO: 19 SEQ ID NO: 20 C3168T 12q14 6 transmembrane domain, voltage gated K+ channel K+Hnov28 SEQ ID NO: 21-24 SEQ ID NO: 25 4 alternative 5' splices 3q29 Modulatory subunit K+Hnov42 SEQ ID NO: 26 SEQ ID NO: 27 G1162A; T1460A; T2496A 8q11 Homology to K+ channel protein of C. elegans K+Hnov44 SEQ ID NO: 28-29 SEQ ID NO: 30 N/A 22p13 beta-subunit. K+Hnov49 SEQ ID NO: 80 SEQ ID NO: 81 (ATCT)n repeats in the 3' 1q41 4T/2P channel; linked to the UTR sequence, starting at disease loci for rippling muscle position 2186 disease 1 (RMD1), and type II pseudohypoaldosteronism K+Hnov59 SEQ ID NO: 82 SEQ ID NO: 83 N/A chr19 4T/2P channel
K+Hnov Nucleic Acid Compositions
[0023]As used herein, the term "K+Hnov" is generically used to refer to any one of the provided genetic sequences listed in Table 1. Where a specific K+Hnov sequence is intended, the numerical designation, e.g. K49 or K59, will be added. Nucleic acids encoding K+Hnov potassium channels may be cDNA or genomic DNA or a fragment thereof. The term "K+Hnov gene" shall be intended to mean the open reading frame encoding any of the provided K+Hnov polypeptides, introns, as well as adjacent 5' and 3' non-coding nucleotide sequences involved in the regulation of expression, up to about 20 kb beyond the coding region, but possibly further in either direction. The gene may be introduced into an appropriate vector for extrachromosomal maintenance or for integration into a host genome.
[0024]The term "cDNA" as used herein is intended to include all nucleic acids that share the arrangement of sequence elements found in native mature mRNA species, where sequence elements are exons and 3' and 5' non-coding regions. Normally mRNA species have contiguous exons, with the intervening introns, when present, removed by nuclear RNA splicing, to create a continuous open reading frame encoding a K+Hnov protein.
[0025]A genomic sequence of interest comprises the nucleic acid present between the initiation codon and the stop codon, as defined in the listed sequences, including all of the introns that are normally present in a native chromosome. It may further include the 3' and 5' untranslated regions found in the mature mRNA. It may further include specific transcriptional and translational regulatory sequences, such as promoters, enhancers, etc., including about 1 kb, but possibly more, of flanking genomic DNA at either the 5' or 3' end of the transcribed region. The genomic DNA may be isolated as a fragment of 100 kbp or smaller; and substantially free of flanking chromosomal sequence. The genomic DNA flanking the coding region, either 3' or 5', or internal regulatory sequences as sometimes found in introns, contains sequences required for proper tissue and stage specific expression.
[0026]The sequence of the 5' flanking region may be utilized for promoter elements, including enhancer binding sites, that provide for developmental regulation in tissues where K+Hnov genes are expressed. The tissue specific expression is useful for determining the pattern of expression, and for providing promoters that mimic the native pattern of expression. Naturally occurring polymorphisms in the promoter regions are useful for determining natural variations in expression, particularly those that may be associated with disease.
[0027]Alternatively, mutations may be introduced into the promoter regions to determine the effect of altering expression in experimentally defined systems. Methods for the identification of specific DNA motifs involved in the binding of transcriptional factors are known in the art, e.g. sequence similarity to known binding motifs, gel retardation studies, etc. For examples, see Blackwell et al. (1995) Mol Med 1: 194-205; Mortlock et al. (1996) Genome Res. 6: 327-33; and Joulin and Richard-Foy (1995) Eur J Biochem 232: 620-626.
[0028]The regulatory sequences may be used to identify cis acting sequences required for transcriptional or translational regulation of K+ Hnov expression, especially in different tissues or stages of development, and to identify cis acting sequences and trans acting factors that regulate or mediate K+Hnov expression. Such transcription or translational control regions may be operably linked to a K+Hnov gene in order to promote expression of wild type or altered K+Hnov or other proteins of interest in cultured cells, or in embryonic, fetal or adult tissues, and for gene therapy.
[0029]The nucleic acid compositions of the subject invention may encode all or a part of the subject polypeptides. Double or single stranded fragments may be obtained of the DNA sequence by chemically synthesizing oligonucleotides in accordance with conventional methods, by restriction enzyme digestion, by PCR amplification, etc. For the most part, DNA fragments will be of at least 15 nt, usually at least 18 nt or 25 nt, and may be at least about 50 nt. Such small DNA fragments are useful as primers for PCR, hybridization screening probes, etc. Larger DNA fragments, i.e. greater than 100 nt are useful for production of the encoded polypeptide. For use in amplification reactions, such as PCR, a pair of primers will be used. The exact composition of the primer sequences is not critical to the invention, but for most applications the primers will hybridize to the subject sequence under stringent conditions, as known in the art. It is preferable to choose a pair of primers that will generate an amplification product of at least about 50 nt, preferably at least about 100 nt. Algorithms for the selection of primer sequences are generally known, and are available in commercial software packages. Amplification primers hybridize to complementary strands of DNA, and will prime towards each other.
[0030]The K+Hnov genes are isolated and obtained in substantial purity, generally as other than an intact chromosome. Usually, the DNA will be obtained substantially free of other nucleic acid sequences that do not include a K+Hnov sequence or fragment thereof, generally being at least about 50%, usually at least about 90% pure and are typically "recombinant", i.e. flanked by one or more nucleotides with which it is not normally associated on a naturally occurring chromosome.
[0031]The DNA may also be used to identify expression of the gene in a biological specimen. The manner in which one probes cells for the presence of particular nucleotide sequences, as genomic DNA or RNA, is well established in the literature and does not require elaboration here. DNA or mRNA is isolated from a cell sample. The mRNA may be amplified by RT-PCR, using reverse transcriptase to form a complementary DNA strand, followed by polymerase chain reaction amplification using primers specific for the subject DNA sequences. Alternatively, the mRNA sample is separated by gel electrophoresis, transferred to a suitable support, e.g. nitrocellulose, nylon, etc., and then probed with a fragment of the subject DNA as a probe. Other techniques, such as oligonucleotide ligation assays, in situ hybridizations, and hybridization to DNA probes arrayed on a solid chip may also find use. Detection of mRNA hybridizing to the subject sequence is indicative of K+Hnov gene expression in the sample.
[0032]The sequence of a K+Hnov gene, including flanking promoter regions and coding regions, may be mutated in various ways known in the art to generate targeted changes in promoter strength, sequence of the encoded protein, etc. The DNA sequence or protein product of such a mutation will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one nucleotide or amino acid, respectively, and may differ by at least two but not more than about ten nucleotides or amino acids. The sequence changes may be substitutions, insertions or deletions. Deletions may further include larger changes, such as deletions of a domain or exon. Other modifications of interest include epitope tagging, e.g. with the FLAG system, HA, etc. For studies of subcellular localization, fusion proteins with green fluorescent proteins (GFP) may be used.
[0033]Techniques for in vitro mutagenesis of cloned genes are known. Examples of protocols for site specific mutagenesis may be found in Gustin et al., Biotechniques 14:22 (1993); Barany, Gene 37:111-23 (1985); Colicelli et al., Mol Gen Genet. 199:537-9 (1985); and Prentki et al., Gene 29:303-13 (1984). Methods for site specific mutagenesis can be found in Sambrook et al., Molecular Cloning: A Laboratory Manual, CSH Press 1989, pp. 15.3-15.108; Weiner et al., Gene 126:35-41 (1993); Sayers et al., Biotechniques 13:592-6 (1992); Jones and Winistorfer, Biotechniques 12:528-30 (1992); Barton et al., Nucleic Acids Res 18:7349-55 (1990); Marotti and Tomich, Gene Anal Tech 6:67-70 (1989); and Zhu, Anal Biochem 177:120-4 (1989). Such mutated genes may be used to study structure-function relationships of K+Hnov, or to alter properties of the protein that affect its function or regulation.
[0034]Homologs and orthologs of K+Hnov genes are identified by any of a number of methods. A fragment of the provided cDNA may be used as a hybridization probe against a cDNA library from the target organism of interest, where low stringency conditions are used. The probe may be a large fragment, or one or more short degenerate primers. Nucleic acids having sequence similarity are detected by hybridization under low stringency conditions, for example, at 50° C. and 6×SSC (0.9 M sodium chloride/0.09 M sodium citrate) and remain bound when subjected to washing at 55° C. in 1×SSC (0.15 M sodium chloride/0.015 M sodium citrate). Sequence identity may be determined by hybridization under stringent conditions, for example, at 50° C. or higher and 0.1×SSC (15 mM sodium chloride/01.5 mM sodium citrate). Nucleic acids having a region of substantial identity to the provided K+Hnov sequences, e.g. allelic variants, genetically altered versions of the gene, etc., bind to the provided K+Hnov sequences under stringent hybridization conditions. By using probes, particularly labeled probes of DNA sequences, one can isolate homologous or related genes. The source of homologous genes may be any species, e.g. primate species, particularly human; rodents, such as rats and mice, canines, felines, bovines, ovines, equines, yeast, nematodes, etc.
[0035]Between mammalian species, e.g. human and mouse, homologs have substantial sequence similarity, i.e. at least 75% sequence identity between nucleotide sequences, in some cases 80 or 90% sequence identity, and may be as high as 95% sequence identity between closely related species. Sequence similarity is calculated based on a reference sequence, which may be a subset of a larger sequence, such as a conserved motif, coding region, flanking region, etc. A reference sequence will usually be at least about 18 nt long, more usually at least about 30 nt long, and may extend to the complete sequence that is being compared. Algorithms for sequence analysis are known in the art, such as BLAST, described in Altschul et al. (1990), J. Mol. Biol. 215:403-10. In general, variants of the invention have a sequence identity greater than at least about 65%, preferably at least about 75%, more preferably at least about 85%, and may be greater than at least about 90% or more as determined by the Smith-Waterman homology search algorithm as implemented in MPSRCH program (Oxford Molecular). Exemplary search parameters for use with the MPSRCH program in order to identify sequences of a desired sequence identity are as follows: gap open penalty: 12; and gap extension penalty: 1.
K+Hnov Polypeptides
[0036]The subject nucleic acid sequences may be employed for producing all or portions of K+Hnov polypeptides. For expression, an expression cassette may be employed. The expression vector will provide a transcriptional and translational initiation region, which may be inducible or constitutive, where the coding region is operably linked under the transcriptional control of the transcriptional initiation region, and a transcriptional and translational termination region. These control regions may be native to a K+Hnov gene, or may be derived from exogenous sources.
[0037]The peptide may be expressed in prokaryotes or eukaryotes in accordance with conventional ways, depending upon the purpose for expression. For large scale production of the protein, a unicellular organism, such as E. coli, B. subtilis, S. cerevisiae, insect cells in combination with baculovirus vectors, or cells of a higher organism such as vertebrates, particularly mammals, e.g. COS 7 cells, may be used as the expression host cells. In some situations, it is desirable to express the K+Hnov gene in eukaryotic cells, where the K+Hnov protein will benefit from native folding and post-translational modifications. Small peptides can also be synthesized in the laboratory. Peptides that are subsets of the complete K+Hnov sequence may be used to identify and investigate parts of the protein important for function, or to raise antibodies directed against these regions.
[0038]Fragments of interest include the transmembrane and pore domains, the signal sequences, regions of interaction between subunits, etc. Such domains will usually include at least about 20 amino acids of the provided sequence, more usually at least about 50 amino acids, and may include 100 amino acids or more, up to the complete domain. Binding contacts may be comprised of non-contiguous sequences, which are brought into proximity by the tertiary structure of the protein. The sequence of such fragments may be modified through manipulation of the coding sequence, as described above. Truncations may be performed at the carboxy or amino terminus of the fragment, e.g. to determine the minimum sequence required for biological activity.
[0039]With the availability of the protein or fragments thereof in large amounts, by employing an expression host, the protein may be isolated and purified in accordance with conventional ways. A lysate may be prepared of the expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique. The purified protein will generally be at least about 80% pure, preferably at least about 90% pure, and may be up to and including 100% pure. Pure is intended to mean free of other proteins, as well as cellular debris.
[0040]The expressed K+Hnov polypeptides are useful for the production of antibodies, where short fragments provide for antibodies specific for the particular polypeptide, and larger fragments or the entire protein allow for the production of antibodies over the surface of the polypeptide. Antibodies may be raised to the wild-type or variant forms of K+Hnov. Antibodies may be raised to isolated peptides corresponding to specific domains, e.g. the pore domain and the to transmembrane domain, or to the native protein.
[0041]Antibodies are prepared in accordance with conventional ways, where the expressed polypeptide or protein is used as an immunogen, by itself or conjugated to known immunogenic carriers, e.g. KLH, pre-S HBsAg, other viral or eukaryotic proteins, or the like. Various adjuvants may be employed, with a series of injections, as appropriate. For monoclonal antibodies, after one or more booster injections, the spleen is isolated, the lymphocytes immortalized by cell fusion, and then screened for high affinity antibody binding. The immortalized cells, i.e. hybridomas, producing the desired antibodies may then be expanded. For further description, see Monoclonal Antibodies: A Laboratory Manual, Harlow and Lane eds., Cold Spring Harbor Laboratories, Cold Spring Harbor, N.Y., 1988. If desired, the mRNA encoding the heavy and light chains may be isolated and mutagenized by cloning in E. coli, and the heavy and light chains mixed to further enhance the affinity of the antibody. Alternatives to in vivo immunization as a method of raising antibodies include binding to phage "display" libraries, usually in conjunction with in vitro affinity maturation.
K+Hnov Genotyping
[0042]The subject nucleic acid and/or polypeptide compositions may be used to genotyping and other analysis for the presence of polymorphisms in the sequence, or variation in the expression of the subject genes. Genotyping may be performed to determine whether a particular polymorphisms is associated with a disease state or genetic predisposition to a disease state, particularly diseases associated with defects in excitatory properties of cells, e.g. cardiac, muscle, renal and neural cells. Disease of interest include rippling muscle disease, and type II psuedohypoaldosteronism.
[0043]Clinical disorders associated with K+ channel defects include long-QT syndrome; a congenital disorder affecting 1 in 10,000-15,000. Affected individuals have a prolonged QT interval in the electrocardiogram due to a delayed repolarization of the ventricle. Genetic linkage analyses identified two loci for long QT syndrome, LQT1, in 11p15.5 and LQT2, in 7q35-36. Positional cloning techniques identified the novel K+ channel KvLQT1 on chromosome 11 while candidate gene analysis identified causative mutations in the HERG K+ channel for LQT2.
[0044]The weaver mouse exhibits several abnormal neurological symptoms, including severe ataxia, loss of granule cell neurons in the cerebellum and dopaminergic cells in the substantia nigra, as well as seizures and male infertility. A G-protein-coupled K+ channel having a mutation in the conserved pore domain has been determined to cause the disease. The pancreatic-islet β-cell ATP-sensitive K+ channel (KATP) is composed of two subunits, the sulfonylurea receptor (SUR) and the inward rectifier K+ channel Kir6.2. Mutations in both SUR and Kir6.2 have been identified in patients with persistent hyperinsulinemic hypoglycemia of infancy, which is caused by unregulated secretion of insulin.
[0045]Genotyping may also be performed for pharmacogenetic analysis to assess the association between an individual's genotype and that individual's ability to react to a therapeutic agent. Differences in target sensitivity can lead to toxicity or therapeutic failure. Relationships between polymorphisms in channel expression or specificity can be used to optimize therapeutic dose administration.
[0046]Genetic polymorphisms are identified in the K+Hnov gene (examples are listed in table 1), e.g. the repeat variation in the 3' UTR of K49. Nucleic acids comprising the polymorphic sequences are used to screen patients for altered reactivity and adverse side effects in response to drugs that act on K+ channels.
[0047]K+Hnov genotyping is performed by DNA or RNA sequence and/or hybridization analysis of any convenient sample from a patient, e.g. biopsy material, blood sample, scrapings from cheek, etc. A nucleic acid sample from an individual is analyzed for the presence of polymorphisms in K+Hnov, particularly those that affect the activity, responsiveness or expression of K+Hnov. Specific sequences of interest include any polymorphism that leads to changes in basal expression in one or more tissues, to changes in the modulation of K+Hnov expression, or alterations in K+Hnov specificity and/or activity.
[0048]The effect of a polymorphism in K+Hnov gene sequence on the response to a particular agent may be determined by in vitro or in vivo assays. Such assays may include monitoring during clinical trials, testing on genetically defined cell lines, etc. The response of an individual to the agent can then be predicted by determining the K+Hnov genotype with respect to the polymorphism. Where there is a differential distribution of a polymorphism by racial background, guidelines for drug administration can be generally tailored to a particular ethnic group.
[0049]Biochemical studies may be performed to determine whether a sequence polymorphism in a K+Hnov coding region or control regions is associated with disease, for example the association of K+Hnov 9 with idiopathic generalized epilepsy. Disease associated polymorphisms may include deletion or truncation of the gene, mutations that alter expression level, that affect the electrical activity of the channel, etc.
[0050]A number of methods are available for analyzing nucleic acids for the presence of a specific sequence. Where large amounts of DNA are available, genomic DNA is used directly. Alternatively, the region of interest is cloned into a suitable vector and grown in sufficient quantity for analysis. The nucleic acid may be amplified by conventional techniques, such as the polymerase chain reaction (PCR), to provide sufficient amounts for analysis. The use of the polymerase chain reaction is described in Saiki et al. (1985) Science 239:487, and a review of current techniques may be found in Sambrook et al. Molecular Cloning: A Laboratory Manual, CSH Press 1989, pp. 14.2-14.33. Amplification may be used to determine whether a polymorphism is present, by using a primer that is specific for the polymorphism. Alternatively; various methods are known in the art that utilize oligonucleotide ligation as a means of detecting polymorphisms, for examples see Riley et al. (1990) N.A.R. 18:2887-2890; and Delahunty et al. (1996) Am. J. Hum. Genet. 58:1239-1246.
[0051]A detectable label may be included in an amplification reaction. Suitable labels include fluorochromes, e.g. fluorescein isothiocyanate (FITC), rhodamine, Texas Red, phycoerythrin, allophycocyanin, 6-carboxyfluorescein (6-FAM), 2',7'-dimethoxy-4',5'-dichloro-6-carboxyfluorescein (JOE), 6-carboxy-X-rhodamine (ROX), 6-carboxy-2',4',7',4,7-hexachlorofluorescein (HEX), 5-carboxyfluorescein (5-FAM) or N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA), radioactive labels, e.g. 32P, 35S, 3H; etc. The label may be a two stage system, where the amplified DNA is conjugated to biotin, haptens, etc. having a high affinity binding partner, e.g. avidin, specific antibodies, etc., where the binding partner is conjugated to a detectable label. The label may be conjugated to one or both of the primers. Alternatively, the pool of nucleotides used in the amplification is labeled, so as to incorporate the label into the amplification product.
[0052]The sample nucleic acid, e.g. amplified or cloned fragment, is analyzed by one of a number of methods known in the art. The nucleic acid may be sequenced by dideoxy or other methods. Hybridization with the variant sequence may also be used to determine its presence, by Southern blots, dot blots, etc. The hybridization pattern of a control and variant sequence to an array of oligonucleotide probes immobilised on a solid support, as described in U.S. Pat. No. 5,445,934; or in WO95/35505, may also be used as a means of detecting the presence of variant sequences. Single strand conformational polymorphism (SSCP) analysis, denaturing gradient gel electrophoresis (DGGE), mismatch cleavage detection, and heteroduplex analysis in gel matrices are used to detect conformational changes created by DNA sequence variation as alterations in electrophoretic mobility. Alternatively, where a polymorphism creates or destroys a recognition site for a restriction endonuclease (restriction fragment length polymorphism, RFLP), the sample is digested with that endonuclease, and the products size fractionated to determine whether the fragment was digested. Fractionation is performed by gel or capillary electrophoresis, particularly acrylamide or agarose gels.
[0053]In one embodiment of the invention, an array of oligonucleotides are provided, where discrete positions on the array are complementary to one or more of the provided sequences, e.g. oligonucleotides of at least 12 nt, frequently 20 nt, or larger, and including the sequence flanking a polymorphic position in a K+Hnov sequence; coding sequences for different K+Hnov channels, panels of ion channels comprising one or more of the provided K+ channels; etc. Such an array may comprise a series of oligonucleotides, each of which can specifically hybridize to a different polymorphism. For examples of arrays, see Hacia et al. (1996) Nature Genetics 14:441-447; Lockhart et al. (1996) Nature Biotechnol. 14:1675-1680; and De Risi et al. (1996) Nature Genetics 14:457-460.
[0054]Screening for polymorphisms in K+Hnov may be based on the functional or antigenic characteristics of the protein. Protein truncation assays are useful in detecting deletions that may affect the biological activity of the protein. Various immunoassays designed to detect polymorphisms in K+Hnov proteins may be used in screening. Where many diverse genetic mutations lead to a particular disease phenotype, functional protein assays have proven to be effective screening tools. The activity of the encoded K+Hnov protein as a potassium channel may be determined by comparison with the wild-type protein.
[0055]Antibodies specific for a K+Hnov may be used in staining or in immunoassays. Samples, as used herein, include biological fluids such as semen, blood, cerebrospinal fluid, tears, saliva, lymph, dialysis fluid and the like; organ or tissue culture derived fluids; and fluids extracted from physiological tissues. Also included in the term are derivatives and fractions of such fluids. The cells may be dissociated, in the case of solid tissues, or tissue sections may be analyzed. Alternatively a lysate of the cells may be prepared.
[0056]Diagnosis may be performed by a number of methods to determine the absence or presence or altered amounts of normal or abnormal K+Hnov polypeptides in patient cells. For example, detection may utilize staining of cells or histological sections, performed in accordance with conventional methods. The antibodies of interest are added to the cell sample, and incubated for a period of time sufficient to allow binding to the epitope, usually at least about 10 minutes. The antibody may be labeled with radioisotopes, enzymes, fluorescers, chemiluminescers, or other labels for direct detection. Alternatively, a second stage antibody or reagent is used to amplify the signal. Such reagents are well known in the art. For example, the primary antibody may be conjugated to biotin, with horseradish peroxidase-conjugated avidin added as a second stage reagent. Alternatively, the secondary antibody conjugated to a flourescent compound, e.g. flourescein, rhodamine, Texas red, etc. Final detection uses a substrate that undergoes a color change in the presence of the peroxidase. The absence or presence of antibody binding may be determined by various methods, including flow cytometry of dissociated cells, microscopy, radiography, scintillation counting, etc.
Modulation Of Gene Expression
[0057]The K+Hnov genes, gene fragments, or the encoded protein or protein fragments are useful in gene therapy to treat disorders associated with K+Hnov defects. Expression vectors may be used to introduce the K+Hnov gene into a cell. Such vectors generally have convenient restriction sites located near the promoter sequence to provide for the insertion of nucleic acid sequences. Transcription cassettes may be prepared comprising a transcription initiation region, the target gene or fragment thereof, and a transcriptional termination' region. The transcription cassettes may be introduced into a variety of vectors, e.g. plasmid; retrovirus, e.g. lentivirus; adenovirus; and the like, where the vectors are able to transiently or stably be maintained in the cells, usually for a period of at least about one day, more usually for a period of at least about several days to several weeks.
[0058]The gene or K+Hnov protein may be introduced into tissues or host cells by any number of routes, including viral infection, microinjection, or fusion of vesicles. Jet injection may also be used for intramuscular administration; as described by Furth et al. (1992) Anal Biochem 205:365-368. The DNA may be coated onto gold microparticles, and delivered intradermally by a particle bombardment device, or "gene gun" as described in the literature (see, for example, Tang et al. (1992) Nature 356:152-154), where gold microprojectiles are coated with the K+Hnov or DNA, then bombarded into skin cells.
[0059]Antisense molecules can be used to down-regulate expression of K+Hnov in cells. The anti-sense reagent may be antisense oligonucleotides (ODN), particularly synthetic ODN having chemical modifications from native nucleic acids, or nucleic acid constructs that express such anti-sense molecules as RNA. The antisense sequence is complementary to the mRNA of the targeted gene, and inhibits expression of the targeted gene products. Antisense molecules inhibit gene expression through various mechanisms, e.g. by reducing the amount of mRNA available for translation, through activation of RNAse H, or steric hindrance. One or a combination of antisense molecules may be administered, where a combination may comprise multiple different sequences.
[0060]Antisense molecules may be produced by expression of all or a part of the target gene sequence in an appropriate vector, where the transcriptional initiation is oriented such that an antisense strand is produced as an RNA molecule. Alternatively, the antisense molecule is a synthetic oligonucleotide. Antisense oligonucleotides will generally be at least about 7, usually at least about 12, more usually at least about 20 nucleotides in length, and not more than about 500, usually not more than about 50, more usually not more than about 35 nucleotides in length, where the length is governed by efficiency of inhibition, specificity, including absence of cross-reactivity, and the like. It has been found that short oligonucleotides, of from 7 to 8 bases in length, can be strong and selective inhibitors of gene expression (see Wagner et al., (1996) Nature Biotechnology 14:840-844).
[0061]A specific region or regions of the endogenous sense strand mRNA sequence is chosen to be complemented by the antisense sequence. Selection of a specific sequence for the oligonucleotide may use an empirical method, where several candidate sequences are assayed for inhibition of expression of the target gene in an in vitro or animal model. A combination of sequences may also be used, where several regions of the mRNA sequence are selected for antisense complementation.
[0062]Antisense oligonucleotides may be chemically synthesized by methods known in the art (see Wagner et al. (1993) supra. and Milligan et al., supra.) Preferred oligonucleotides are chemically modified from the native phosphodiester structure, in order to increase their intracellular stability and binding affinity. A number of such modifications have been described in the literature, which alter the chemistry of the backbone, sugars or heterocyclic bases.
[0063]Among useful changes in the backbone chemistry are phosphorothioates; phosphorodithioates, where both of the non-bridging oxygens are substituted with sulfur; phosphoroamidites; alkyl phosphotriesters and boranophosphates. Achiral phosphate derivatives include 3'-O'-5'-S-phosphorothioate, 3'-S-5'-O-phosphorothioate, 3'-CH2-5'-O-phosphonate and 3'-NH-5'-O-phosphoroamidate. Peptide nucleic acids replace the entire ribose phosphodiester backbone with a peptide linkage. Sugar modifications are also used to enhance stability and affinity. The α-anomer of deoxyribose may be used, where the base is inverted with respect to the natural β-anomer. The 2'-OH of the ribose sugar may be altered to form 2'-O-methyl or 2'-O-allyl sugars, which provides resistance to degradation without comprising affinity. Modification of the heterocyclic bases must maintain proper base pairing. Some useful substitutions include deoxyuridine for deoxythymidine; 5-methyl-2'-deoxycytidine and 5-bromo-2'-deoxycytidine for deoxycytidine. 5-propynyl-2'-deoxyuridine and 5-propynyl-2'-deoxycytidine have been shown to increase affinity and biological activity when substituted for deoxythymidine and deoxycytidine, respectively.
[0064]As an alternative to anti-sense inhibitors, catalytic nucleic acid compounds, e.g. ribozymes, anti-sense conjugates, etc. may be used to inhibit gene expression. Ribozymes may be synthesized in vitro and administered to the patient, or may be encoded on an expression vector, from which the ribozyme is synthesized in the targeted cell (for example, see International patent application WO 9523225, and Beigelman et al. (1995) Nucl. Acids Res 23:4434-42). Examples of oligonucleotides with catalytic activity are described in WO 9506764. Conjugates of anti-sense ODN with a metal complex, e.g. terpyridylCu(II), capable of mediating mRNA hydrolysis are described in Bashkin et al. (1995) Appl Biochem Biotechnol 54:43-56.
Genetically Altered Cell Or Animal Models For K+Hnov Function
[0065]The subject nucleic acids can be used to generate transgenic animals or site specific gene modifications in cell lines. Transgenic animals may be made through homologous recombination, where the normal K+Hnov locus is altered. Alternatively, a nucleic acid construct is randomly integrated into the genome. Vectors for stable integration include plasmids, retroviruses and other animal viruses, YACs, and the like.
[0066]The modified cells or animals are useful in the study of K+Hnov function and regulation. For example, a series of small deletions and/or substitutions may be made in the K+Hnov gene to determine the role of different transmembrane domains in forming multimeric structures, ion channels, etc. Of interest are the use of K+Hnov to construct transgenic animal models for epilepsy and other neurological defects, where expression of K+Hnov is specifically reduced or absent. Specific constructs of interest include anti-sense K+Hnov, which will block K+Hnov expression, expression of dominant negative K+Hnov mutations, etc. One may also provide for expression of the K+Hnov gene or variants thereof in cells or tissues where it is not normally expressed or at abnormal times of development.
[0067]DNA constructs for homologous recombination will comprise at least a portion of the K+Hnov gene with the desired genetic modification, and will include regions of homology to the target locus. DNA constructs for random integration need not include regions of homology to mediate recombination. Conveniently, markers for positive and negative selection are included. Methods for generating cells having targeted gene modifications through homologous recombination are known in the art. For various techniques for transfecting mammalian cells, see Keown et at (1990) Methods in Enzymology 185:527-537.
[0068]For embryonic stem (ES) cells, an ES cell line may be employed, or embryonic cells may be obtained freshly from a host, e.g. mouse, rat, guinea pig, etc. Such cells are grown on an appropriate fibroblast-feeder layer or grown in the presence of leukemia inhibiting factor (LIF). When ES or embryonic cells have been transformed, they may be used to produce transgenic animals. After transformation, the cells are plated onto a feeder layer in an appropriate medium. Cells containing the construct may be detected by employing a selective medium. After sufficient time for colonies to grow, they are picked and analyzed for the occurrence of homologous recombination or integration of the construct. Those colonies that are positive may then be used for embryo manipulation and blastocyst injection. Blastocysts are obtained from 4 to 6 week old superovulated females. The ES cells are trypsinized, and the modified cells are injected into the blastocoel of the blastocyst. After injection, the blastocysts are returned to each uterine horn of pseudopregnant females. Females are then allowed to go to term and the resulting offspring screened for the construct. By providing for a different phenotype of the blastocyst and the genetically modified cells, chimeric progeny can be readily detected.
[0069]The chimeric animals are screened for the presence of the modified gene and males and females having the modification are mated to produce homozygous progeny. If the gene alterations cause lethality at some point in development, tissues or organs can be maintained as allogeneic or congenic grafts or transplants, or in in vitro culture. The transgenic animals may be any non-human mammal, such as laboratory animals, domestic animals, etc. The transgenic animals may be used in functional studies, drug screening, etc., e.g. to determine the effect of a candidate drug on Ras or related gene activation, oncogenesis, etc.
Testing Of K+Hnov Function And Responses
[0070]Potassium channels such as K+Hnov polypeptides are involved in multiple biologically important processes. Pharmacological agents designed to affect only specific channel subtypes are of particular interest. Presently available compounds tend to be non-specific and elicit both positive and negative responses, thereby reducing clinical efficacy.
[0071]The subject polypeptides may be used in in vitro and in vivo models to test the specificity of novel compounds, and of analogs and derivatives of compounds known to act on potassium channels. Numerous pharmacological agents have profound affects on K+ channel activity. As examples, Sotalol (BETAPACE) is a class III antiarrhythmic drug that prolongs cardiac action potentials by inhibiting delayed rectifier K+ channels. Sulfonylurea drugs, such as Glipizide (GLUCOTROL) and Tolazamide (TOLAMIDE) function as antidiabetic drugs by blocking ATP-sensitive K+ channels present in pancreatic islet cells, thereby regulating insulin secretion. Diazoxide (HYPERSTAT IV) is an antihypertensive drug that activates ATP-sensitive K+ channels, resulting in the relaxation of vascular smooth muscle. There are several other examples of drugs that have antidiabetic, antihypertensive, or antiarrhythmic activities. A number of drugs that activate. K+ channels that have been proposed as coronary vasodilators for the treatment of both vasospastic and chronic stable angina.
[0072]The availability of multiple K+ channel subunits allows in vitro reconstruction of functional channels, which may comprise different alpha and beta subunits. The individual components may be modified by sequence deletion, substitution, etc. to determine the functional role of specific domains.
[0073]Drug screening may be performed using an in vitro model, a genetically altered cell or animal, or purified K+Hnov protein, either as monomers, homomultimers or hetermultimers. One can identify ligands or substrates that bind to, modulate or mimic the action of K+Hnov. Drug screening identifies agents that provide a replacement for K+Hnov function in abnormal cells. Of particular interest are screening assays for agents that have a low toxicity for human cells. A wide variety of assays may be used for this purpose, including monitoring cellular excitation and conductance, labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, and the like. The purified protein may also be used for determination of three-dimensional crystal structure, which can be used for modeling intermolecular interactions.
[0074]The term "agent" as used herein describes any molecule, e.g. protein or pharmaceutical, with the capability of altering or mimicking the physiological function of K+Hnov polypeptide. Generally a plurality of assay mixtures are run in parallel with different agent concentrations to obtain a differential response to the various concentrations. Typically, one of these concentrations serves as a negative control, i.e. at zero concentration or below the level of detection.
[0075]Candidate agents encompass numerous chemical classes, though typically they are organic molecules, preferably small organic compounds having a molecular weight of more than 50 and less than about 2,500 daltons. Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups. The candidate agents often comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof.
[0076]Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means, and may be used to produce combinatorial libraries. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc. to produce, structural analogs.
[0077]Where the screening assay is a binding assay, one or more of the molecules may be joined to a label, where the label can directly or indirectly provide a detectable signal. Various labels include radioisotopes, fluorescers, chemiluminescers, enzymes, specific binding molecules, particles, e.g. magnetic particles, and the like. Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc. For the specific binding members, the complementary member would normally be labeled with a molecule that provides for detection, in accordance with known procedures.
[0078]A variety of other reagents may be included in the screening assay. These include reagents like salts, neutral proteins, e.g. albumin, detergents, etc that are used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions. Reagents that improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc. may be used. The mixture of components are added in any order that provides for the requisite binding. Incubations are performed at any suitable temperature, typically between 4 and 40° C. Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high-throughput screening. Typically between 0.1 and 1 hours will be sufficient.
[0079]The compounds having the desired pharmacological activity may be administered in a physiologically acceptable carrier to a host in a variety of ways, orally, topically, parenterally e.g. subcutaneously, intraperitoneally, by viral infection, intravascularly, etc. Depending upon the manner of introduction, the compounds may be formulated in a variety of ways. The concentration of therapeutically active compound in the formulation may vary from about 0.1-100 wt. %. The pharmaceutical compositions can be prepared in various forms, such as granules, tablets, pills, suppositories, capsules, suspensions, salves, lotions and the like. Pharmaceutical grade organic or inorganic carriers and/or diluents suitable for oral and topical use can be used to make up compositions containing the therapeutically-active compounds. Diluents known to the art include aqueous media, vegetable and animal oils and fats. Stabilizing agents, wetting and emulsifying agents, salts for varying the osmotic pressure or buffers for securing an adequate pH value, and skin penetration enhancers can be used as auxiliary agents.
[0080]It is to be understood that this invention is not limited to the particular methodology, protocols, cell lines, animal species or genera, and reagents described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.
[0081]As used herein the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the cell" includes reference to one or more cells and equivalents thereof known to those skilled in the art, and so forth. All technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs unless clearly indicated otherwise.
[0082]It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a complex" includes a plurality of such complexes and reference to "the formulation" includes reference to one or more formulations and equivalents thereof known to those skilled in the art, and so forth.
[0083]All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing, for example, the methods and methodologies that are described in the publications which might be used in connection with the presently described invention. The publications discussed above and throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.
EXPERIMENTAL
[0084]The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the subject invention, and are not intended to limit the scope of what is regarded as the invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g. amounts, temperature, concentrations, etc.) but some experimental errors and deviations should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees centigrade; and pressure is at or near atmospheric.
Methods
[0085]Two different types of sequence searches were performed. The first centered on the most highly conserved region of the K+ channel family, the pore domain. The pore is composed of 15-17 amino acids and can be divided into subfamilies based on the number of transmembrane segments present in the channel. Eleven variant peptide sequences corresponding to the pore domain were used in TBLASTN searches against the EST division of Genbank. Significant matches were identified, and classified into 2 categories: identical to known human K+ channels and related to known K+ channels. The pore sequences are shown in Table 2.
TABLE-US-00002 TABLE 2 SEQ ID Genbank NO # 49 L02751 TGGTGGGCTGTGGTGACCATGACAACTGTGGG CTATGGGGACATG 50 M60451 TGGTGGGCAGTGGTCACCATGACCACTGTGGG CTACGGGGACATG 51 L02752 TGGTGGGCAGTCGTCTCCATGACAACTGTAGG CTATGGAGACATG 52 M55515 TGGTGGGCAGTGGTAACCATGACAACAGTGGG TTACGGCGATATG 53 Z11585 TGGTGGGCTGTGGTCACCATGACGACCCTGGG CTATGGAGACATG 54 U40990 TGGTGGGGGGTGGTCACAGTCACCACCATCGG CTATGGGGACAAG 55 I26643 TGGTGGGCAGTGGTCACCATGACCACGGTTGG CTATGGGGACATG 56 M96747 TGGTGGGCCGTGGTCACCATGACGACCCTGGG CTATGGAGACATG 57 M64676 TGGTGGGCTGTGGTCACCATGACGACACTGGG CTACGGAGACATG 58 M55514 TGGTGGGCTGTGGTGACCATGACAACTGTGGG CTATGGGGACATG 59 X83582 TTCCTGTTCTCCATTGAGACCGAAACAACCAT TGGGTATGGCTTCCG 60 S78684 TTTTTATTCTCAATAGAGACAGAAACCACCAT TGGTTATGGCTACCG 61 U22413 TTCCTCTTCTCCATTGAGACCCAGACAACCAT AGGCTATGGTTTCAG 62 U24056 TTCCTGTTCTCGGTGGAGACGCAGACGACCAT CGGCTATGGGTTCCG 63 U52155 TTCCTCTTCTCCCTTGAATCCCAAACCACCAT TGGCTATGGCTTCCG 64 D87291 TTTCTCTTTTCCCTGGAATCCCAGACAACCAT TGGCTATGGAGTCCG 65 D50582 TTCCTTTTCTCCATTGAGGTCCAAGTGACTAT TGGCTTTGGGGGGCG 66 D50315 TTTCTCTTCTCCATTGAAGTTCAAGTTACCAT TGGGTTTGGAGGGAG 67 U04270 GCGCTCTACTTCACCTTCAGCAGCCTCACCAG TGTGGGCTTCGGCAAC
[0086]The unique pore peptides sequences are shown in Table 3
TABLE-US-00003 TABLE 3 SEQ ID NO Amino Acid sequence 68 WWAVVSMTTVGYGDM 69 WWAVVTMTTLGYGDM 70 WWGVVTVTTIGYGDK 71 WWAVVTMTTVGYGDM 72 FLFSIEVQVTIGFGG 73 FLFSLESQTTIGYGV 74 FLFSIETETTIGYGY 75 FLFSIETQTTIGYGF 76 FLFSVETQTTIGYGF 77 FLFSLESQTTIGYGF 78 FLFSIETETTIGYGF 79 ALYFTFSSLTSVGFGN
[0087]The second set of experiments was based on a complex, reiterative process. Annotated protein and DNA sequences were obtained from GenBank for all known K+ channels from all species. The TBLASTN and BLASTN programs were used to identify homologous ESTs, which were then analyzed using the BLASTX and BLASTN algorithms to identify ESTs which were related to K+ channels yet not identical to any known human K+ channel gene.
[0088]Novel human K+ channels were defined as those that had clear homology to known K+ channels from any species and were not present as identities or near identities to any human-derived sequences in any division of Genbank.
[0089]Isolation of full length cDNA sequence. EST clones were picked from the IMAGE consortium cDNA library and end-sequenced with vector primers. Gap closure was achieved either by primer walking or transposon sequencing. GeneTrapper (Life Technologies) was used to isolate larger cDNA clones according to the provided protocol. RACE was used to extend the sequences as necessary using standard protocols
[0090]Sequences were assembled in Sequencher (Gene Codes). The presence of open reading frames was assessed as well as potential start codons. Potential polymorphisms were detected as sequence variants between multiple independent clones. Sequence homologies were detected using the BLAST algorithms.
[0091]The completed gene sequences and predicted amino acid sequences are provided as SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21-24, 26 and 28-29. Polymorphisms, chromosome locations and family assignments are shown in Table 1.
[0092]ESTs that had top human hits with >95% identity over 100 amino acids were discarded. This was based upon the inventors' experience that these sequences were usually identical to the starting probe sequences, with the differences due to sequence error. The remaining BLASTN and BLASTX outputs for each EST were examined manually, i.e., ESTs were removed from the analysis if the inventors determined that the variation from the known related probe sequence was a result of poor database sequence. Poor database sequence was usually identified as a number of `N` nucleotides in the database sequence for a BLASTN search and as a base deletion or insertion in the database sequence, resulting in a peptide frameshift, for a BLASTX output. ESTs for which the highest scoring match was to non-related sequences were also discarded at this stage. The EST sequences that correspond to each done are shown in Table 4.
TABLE-US-00004 TABLE 4 Genbank IMAGE Plate Accession# K + Hnov clone ID Trace Coordinates Read 5'/3' N39619 K + Hnov2 277113 yy51h05.s1 611p10 3' N46767 K + Hnov2 277113 yy51h05.r1 611p10 5' R19352 K + Hnov11 33144 yg24f12.r1 155o24 5' R44628 K + Hnov11 33144 yg24f12.s1 155o24 3' R35526 K + Hnov14 37299 yg64e08.r1 165o15 5' R73353 K + Hnov14 157854 yl10e04.r1 251g07 5' AA397616 K + Hnov14 728558 zt79c08.r1 1787j15 5' AA286692 K + Hnov28 700757 zs48h03.r1 1715d6 5' AA150494 K + Hnov42 491748 zl08e07.s1 1170o13 3' AA156697 K + Hnov42 491748 zl08e07.r1 1170o13 5' AA191752 K + Hnov42 626699 zp82d06.r1 1522f12 5' AA216446 K + Hnov42 626699 zp82d06.s1 1522f12 3' AA430591 K + Hnov42 773611 zw51f10.r1 1904o20 5' AA236930 K + Hnov44 683888 zs01a05.s1 1671e9 3' AA236968 K + Hnov44 683888 zs01a05.r1 1671e9 5'
Example 2
Chromosomal Localization
[0093]Two primers were designed in the 3'-untranslated regions of each gene sequence to amplify a product across the Stanford G3 radiation hybrid map, or the Whitehead GB4 panel. The PCR data were submitted for automatic two-point analysis. Mapping data were correlated with cytoband information and comparisons with the OMIM human gene map data base were made. The following primers were made:
TABLE-US-00005 K + Hnov1 on GB4 (SEQ ID NO: 31) F: 5' TATCCACATCAATGGACAAAGC 3' (SEQ ID NO: 32) R: 5' TGCATAACTGGCTGGGTGTA 3' Results: 1.71 cR from D2S331, Cytogenetic location of 2q37 K + Hnov2 on G3 F: 5' GTCAGGTGACCGAGTTCA 3' R: 5' GCTCCATCTCCAGATTCTTC 3' Results: 0.0 cR from SHGC-1320, Cytogenetic location of 11q12 K + Hnov6 on GB4 (SEQ ID NO: 33) F: 5' TGACATCACTGGATGAACTTGA 3' (SEQ ID NO: 34) R: 5' TGCCTGCAAAGTTTGAACAT 3' Results: 5.23 cR from WI-5509, Cytogenetic location of 2p23 K + Hnov9 on GB4 (SEQ ID NO: 35) F: 5' TGACATCACTGGATGAACTTGA 3' (SEQ ID NO: 36) R: 5' TGCCTGCAAAGTTTGAACAT 3' Results 1.21 cR from AFM200VC 7, Cytogenetic location of 8q23 K + Hnov11 on GB4 (SEQ ID NO: 37) F: 5' ACCTGGTGGTATGGAAGCAT 3' (SEQ ID NO: 38) R: 5' TTTCTCCTGGCCTCTACCC 3' Results: 2.43 cR from WI-6756, Cytogenetic location of 8q23 K + Hnov12 on G3 (SEQ ID NO: 39) F: 5' TCCCTCTTGGGTGACCTTC 3' (SEQ ID NO: 40) R: 5' ATCTTTGTCAGCCACCAGCT 3' Results: 7.45 cR from SHGC-32925, Cytogenetic location of Xp21 K + Hnov14 on GB4 (SEQ ID NO: 41) F: 5' AGGTGTGCTGCCATCTGCTGTTCG3' (SEQ ID NO: 42) R: 5' AGCCTATCCTCTCTGAGAGTCAGG Results: 7.69 cR from WI-7107, Cytogenetic location of 12q14 K + Hnov28 on GB4 (SEQ ID NO: 43) F: 5' AAGCAGAGTACTCATGATGCC 3' (SEQ ID NO: 44) R: 5' TCTGGTAGACAGTACAGTGG 3' Results: 35.38 cR from WI-9695, Cytogenetic location of 3q29 K + Hnov42 on G3 (SEQ ID NO: 45) F: 5' CATTTGGCTGGTCCAAGATG 3' (SEQ ID NO: 46) R: 5' AGTCATTGGTAGGGAGGTAC 3' Results: 7.45 cR from SHGC-32925, Cytogenetic location of Xp21 K + Hnov44 on G3 (SEQ ID NO: 47) F: 5' CATGCTTCTACAGTCCAGCC 3' (SEQ ID NO: 48) R: 5' GGTCCTCAGTTGCAGAAATC 3' Results: 7.45 cR from SHGC-32925, Cytogenetic location of Xp21
Map positions for K+Hnov15 and K+Hnov27 were obtained from public databases. K+Hnov2 and K+Hnov4 have not been mapped.
Example 3
Expression Analysis
[0094]RT-PCR was utilized to characterize the expression pattern of the novel ion channels. This approach used RNA from 30 different tissues to generate first strand cDNA. Total RNA was purchased (Clontech, Invitrogen) and used to synthesize first strand cDNA using M-MLV reverse transcriptase and the supplied buffer (Gibco-BRL). The 20 μl reaction contained 5 μg total RNA, 100 ng of random primers, 10 mM DTT, 0 5 mM each dNTP, and an RNAse inhibitor (Gibco-BRL). Identical reactions were set up without reverse transcriptase to control for DNA contamination in the RNA samples. The synthesis reaction proceeded for 1 hour at 37° C. followed by 10 minutes at 95° C. These cDNAs, along with control cDNA synthesis reactions without reverse transcriptase, were diluted 1:5 and 2 μl of each sample were arrayed into 96-well trays, dried, and resuspended in PCR buffer prior to PCR amplification. The cDNAs were tested with primers with defined expression patterns to verify the presence of amplifiable cDNA from each tissue. Gene-specific primers were used to amplify the cDNAs in 20 μl PCR reactions with standard conditions, 2.5 mM MgCl2, Taq Gold, and an appropriate annealing temperature.
[0095]This approach provides for relatively high-throughput analysis of gene expression in a large set of tissues in a cost-efficient manner and provides qualitative analysis of gene expression only. Modifications can be employed, such as the use of internal control primers, limited cycling parameters, and dilution series to convert this to a quantitative experiment.
TABLE-US-00006 TABLE 3 ##STR00001## A "+" indicates expression in the tissue, a "-" indicates no expression, and blank square indicates no data for that sample.
TABLE-US-00007 K + Hnov49 on Whitehead GB4 RH mapping panel: Primer 1 (SEQ ID NO: 5): 5' - CATAGCCATAGGTGAGGACT - 3' Primer 2: (SEQ ID NO: 6) 5' - GAGAGGAAAACAGTCTGGGC - 3' Results: Cytogenetic location 1q41, 4.6 cR from framework marker D1S217 K + Hnov59 on Whitehead GB4 RH mapping panel Primer 1 (SEQ ID NO: 7): 5' - GGACATCGAACTAAGACCTG - 3' Primer 2 (SEQ ID NO: 8): 5' - TCCCATGCCATTCAGATCTG - 3' Results: Cytogenetic location 19q13.2. 8.34 cr from framework marker D19S425
Expression Analysis Of K+Hnov49
[0096]A probe was created from a fragment corresponding to nucleotides 50 to 1284 of SEQ ID NO:83 (K+Hnov49) and purified DNA fragment was labeled with [32P]dCTP (Amersham) by the random primer method. Adult human Multiple Tissue Northern (MTM®) Blots (Clontech) were hybridized with the [32P]-labeled fragment in ExpressHyb® solution (Clontech) for four hours, washed to a final stringency of 0.1×SSC, 0.1% SDS at 65° C. and subjected to autoradiography for 24 hours.
[0097]Analysis revealed that K+Hnov49 is expressed as an approximately 4.2 kb mRNA. Expression levels of K+Hnov49 are high in brain and liver and low in kidney tissues. No mRNA was detectable on these Northern blots for heart, skeletal muscle, colon, thymus, spleen, small intestine, placenta, lung or peripheral blood leukocytes indicating either a very low level of expression or that it is not expressed in these tissues. Expression analysis is was also carried out by RT-PCR across an extended series of tissues. The results of these analyses are shown in Table 4. Primer pairs used for amplification of K+Hnov49 and 59 are the same as those used for RH mapping as indicated above.
TABLE-US-00008 TABLE 4 Adrenal Fetal Fetal HeLa Adipose Gland Bladder Brain Cerebellum Cervix Colon Esophagus Brain Liver Heart Cell #49 + + + + + + - + + - + + #59 - - - - - + - + - + + - Mammary Salivary Skeletal Kidney Liver Lung Gland Pancreas Placenta Prostate Rectum Gland Muscle Skin #49 + - + + - - + - + + - #59 - + + + + - + + + - - Small Intestine Spleen Stomach Testis Thymus Trachea Uterus #49 + - + + + - - #59 + + + + + + +
Sequence CWU
1
8712932DNAH. sapiensCDS(103)...(1180)K+Hnov1 1attaaaatta tctgatcaaa
aaggcagact ctgtaaattt ccttaagacc taccttggca 60taaaggctga cccagcaaaa
gaactgagaa atacagcctg ag atg gac agc agt 114Met Asp Ser Ser1aat tgc
aaa gtt att gct cct ctc cta agt caa aga tac cgg agg atg 162Asn Cys
Lys Val Ile Ala Pro Leu Leu Ser Gln Arg Tyr Arg Arg Met5
10 15 20gtc acc aag gat ggc cac agc
aca ctt caa atg gat ggc gct caa aga 210Val Thr Lys Asp Gly His Ser
Thr Leu Gln Met Asp Gly Ala Gln Arg 25 30
35ggt ctt gca tat ctt cga gat gct tgg gga atc cta atg
gac atg cgc 258Gly Leu Ala Tyr Leu Arg Asp Ala Trp Gly Ile Leu Met
Asp Met Arg 40 45 50tgg cgt
tgg atg atg ttg gtc ttt tct gct tct ttt gtt gtc cac tgg 306Trp Arg
Trp Met Met Leu Val Phe Ser Ala Ser Phe Val Val His Trp 55
60 65ctt gtc ttt gca gtg ctc tgg tat gtt ctg
gct gag atg aat ggt gat 354Leu Val Phe Ala Val Leu Trp Tyr Val Leu
Ala Glu Met Asn Gly Asp 70 75 80ctg
gaa cta gat cat gat gcc cca cct gaa aac cac act atc tgt gtc 402Leu
Glu Leu Asp His Asp Ala Pro Pro Glu Asn His Thr Ile Cys Val85
90 95 100aag tat atc acc agt ttc
aca gct gca ttc tcc ttc tcc ctg gag aca 450Lys Tyr Ile Thr Ser Phe
Thr Ala Ala Phe Ser Phe Ser Leu Glu Thr 105
110 115caa ctc aca att ggt tat ggt acc atg ttc ccc agt
ggt gac tgt cca 498Gln Leu Thr Ile Gly Tyr Gly Thr Met Phe Pro Ser
Gly Asp Cys Pro 120 125 130agt
gca atc gcc tta ctt gcc ata caa atg ctc cta ggc ctc atg cta 546Ser
Ala Ile Ala Leu Leu Ala Ile Gln Met Leu Leu Gly Leu Met Leu 135
140 145gag gct ttt atc aca ggt gct ttt gtg
gcg aag att gcc cgg cca aaa 594Glu Ala Phe Ile Thr Gly Ala Phe Val
Ala Lys Ile Ala Arg Pro Lys 150 155
160aat cga gct ttt tca att cgc ttt act gac aca gca gta gta gct cac
642Asn Arg Ala Phe Ser Ile Arg Phe Thr Asp Thr Ala Val Val Ala His165
170 175 180atg gat ggc aaa
cct aat ctt atc ttc caa gtg gcc aac acc cga cct 690Met Asp Gly Lys
Pro Asn Leu Ile Phe Gln Val Ala Asn Thr Arg Pro 185
190 195agc cct cta acc agt gtc cgg gtc tca gct
gta ctc tat cag gaa aga 738Ser Pro Leu Thr Ser Val Arg Val Ser Ala
Val Leu Tyr Gln Glu Arg 200 205
210gaa aat ggc aaa ctc tac cag acc agt gtg gat ttc cac ctt gat ggc
786Glu Asn Gly Lys Leu Tyr Gln Thr Ser Val Asp Phe His Leu Asp Gly
215 220 225atc agt tct gac gaa tgt cca
ttc ttc atc ttt cca cta acg tac tat 834Ile Ser Ser Asp Glu Cys Pro
Phe Phe Ile Phe Pro Leu Thr Tyr Tyr 230 235
240cac tcc att aca cca tca agt cct ctg gct act ctg ctc cag cat gaa
882His Ser Ile Thr Pro Ser Ser Pro Leu Ala Thr Leu Leu Gln His Glu245
250 255 260aat cct tct cac
ttt gaa tta gtt gta ttc ctt tca gca atg cag gag 930Asn Pro Ser His
Phe Glu Leu Val Val Phe Leu Ser Ala Met Gln Glu 265
270 275ggc act gga gaa ata tgc caa agg agg aca
tcc tac cta ccg tct gaa 978Gly Thr Gly Glu Ile Cys Gln Arg Arg Thr
Ser Tyr Leu Pro Ser Glu 280 285
290atc atg tta cat cac tgt ttt gca tct ctg ttg acc cga ggt tcc aaa
1026Ile Met Leu His His Cys Phe Ala Ser Leu Leu Thr Arg Gly Ser Lys
295 300 305ggt gaa tat caa atc aag atg
gag aat ttt gac aag act gtc cct gaa 1074Gly Glu Tyr Gln Ile Lys Met
Glu Asn Phe Asp Lys Thr Val Pro Glu 310 315
320ttt cca act cct ctg gtt tct aaa agc cca aac agg act gac ctg gat
1122Phe Pro Thr Pro Leu Val Ser Lys Ser Pro Asn Arg Thr Asp Leu Asp325
330 335 340atc cac atc aat
gga caa agc att gac aat ttt cag atc tct gaa aca 1170Ile His Ile Asn
Gly Gln Ser Ile Asp Asn Phe Gln Ile Ser Glu Thr 345
350 355gga ctg aca g aataagactt atccattttt
taatgtatta aatacaccca 1220Gly Leu Thrgccagttatg cagctacttt
ttctttactg tatctcatgt tttctttttt caatgctaat 1280tatagctctc tacatcacgg
taatcatgcc tatgcctaca taagaatggc tgagctaaca 1340atacacattc tggaaacata
acactctaca ttacaaagtt tgttacctgc tgaaatcaat 1400gtaactcaac ttgacagaca
cttatacaga aatgttgctg gtgaatttat aagaatgtgg 1460tatgatacta gtaatgaagg
caaaatggac agtgaagttt aacacaactg aactctaaga 1520aaatcaacca ttaatctctc
attttcatct gcaaattgaa gcaacagttt agtttcaaac 1580ctagctccct gggtggaatg
acgacttcac tatacttagt gaatatcctt taagagctgg 1640gatttttttc aagacaacaa
agatcattca tttggttctt tatactatga aacttgagta 1700agtattacct ccttaatttt
taacaactaa gaacaaaaat taacgagaaa aacaacaaag 1760tacagattta tacataaacc
taaaagcatt tgaacatgac acccgaacac atacatatat 1820gttcacttat ttgtggcaga
aggtgatcag ataagctcca gcccaaatgg aacctgtggg 1880gtggtatttt gcattgcaag
gagacgcaaa attttatttt aaaactgtcc tccataataa 1940tcaaacggtg attcatctaa
atgacttcta gcaacctaag taaaaacatt cccctcctat 2000gtatgattca tttgatcata
taaaacatca tgatggctct aattcataaa tacaaaaata 2060tatttaagtc tttatagata
taaagcttta cttagatata acttgagtga gtagggaaaa 2120aaatctacag tagataaagc
aaaagataat taggcaacaa agcattttca aactcaaatt 2180cctgtttcca acttcaaata
gttttttcta taaacacaaa atcagtgttt attcaccagt 2240aggaggttgg actagatgaa
ctctattatt tctttctaaa tctaatagtc tataaaaatt 2300atgtttcctc tgttttttat
tttatctatg ctaaaatgag ccctttccct tatgtccagt 2360ttaagatgat catttgcatg
attttcattt caataaaaaa aagagaaact gtccttaaaa 2420caaaacaaaa accaaaaaag
tcaccctatc aggtttcaaa cagatttgtg gctgttcttt 2480tctgaaattt cccttattca
ggtttctgtg ggaaaaatga aagattaacc ttccccactg 2540gtgatgacct aggcaggaat
catctcttga aataaatact agctgagtaa aggcaagcag 2600gtgtgaagag cagggctcag
cagcaagtca catttttcta ctatttgacc aaaaggaaaa 2660gaaaataaag aagaactctg
gagtggtcta agactgataa tagcagaaga atatcaagaa 2720cacagaaact taattattgt
gaacttttgc tgtttgaaaa tcttagacat tcattcttaa 2780gtagaaatca gaccaacaga
ttttcccaac ccaagactat tgtaacacat aaagacagca 2840agaattctta tttctataat
aaattaacaa gattcaccta acctttgaaa ataaagtagt 2900attgaagact taaaaaaaaa
aaaaaaaaaa aa 29322359PRTH. sapiens 2Met
Asp Ser Ser Asn Cys Lys Val Ile Ala Pro Leu Leu Ser Gln Arg1
5 10 15Tyr Arg Arg Met Val Thr Lys Asp
Gly His Ser Thr Leu Gln Met Asp 20 25
30Gly Ala Gln Arg Gly Leu Ala Tyr Leu Arg Asp Ala Trp Gly Ile
Leu 35 40 45Met Asp Met Arg Trp
Arg Trp Met Met Leu Val Phe Ser Ala Ser Phe 50 55
60Val Val His Trp Leu Val Phe Ala Val Leu Trp Tyr Val Leu
Ala Glu65 70 75 80Met
Asn Gly Asp Leu Glu Leu Asp His Asp Ala Pro Pro Glu Asn His
85 90 95Thr Ile Cys Val Lys Tyr Ile
Thr Ser Phe Thr Ala Ala Phe Ser Phe 100 105
110Ser Leu Glu Thr Gln Leu Thr Ile Gly Tyr Gly Thr Met Phe
Pro Ser 115 120 125Gly Asp Cys Pro
Ser Ala Ile Ala Leu Leu Ala Ile Gln Met Leu Leu 130
135 140Gly Leu Met Leu Glu Ala Phe Ile Thr Gly Ala Phe
Val Ala Lys Ile145 150 155
160Ala Arg Pro Lys Asn Arg Ala Phe Ser Ile Arg Phe Thr Asp Thr Ala
165 170 175Val Val Ala His Met
Asp Gly Lys Pro Asn Leu Ile Phe Gln Val Ala 180
185 190Asn Thr Arg Pro Ser Pro Leu Thr Ser Val Arg Val
Ser Ala Val Leu 195 200 205Tyr Gln
Glu Arg Glu Asn Gly Lys Leu Tyr Gln Thr Ser Val Asp Phe 210
215 220His Leu Asp Gly Ile Ser Ser Asp Glu Cys Pro
Phe Phe Ile Phe Pro225 230 235
240Leu Thr Tyr Tyr His Ser Ile Thr Pro Ser Ser Pro Leu Ala Thr Leu
245 250 255Leu Gln His Glu
Asn Pro Ser His Phe Glu Leu Val Val Phe Leu Ser 260
265 270Ala Met Gln Glu Gly Thr Gly Glu Ile Cys Gln
Arg Arg Thr Ser Tyr 275 280 285Leu
Pro Ser Glu Ile Met Leu His His Cys Phe Ala Ser Leu Leu Thr 290
295 300Arg Gly Ser Lys Gly Glu Tyr Gln Ile Lys
Met Glu Asn Phe Asp Lys305 310 315
320Thr Val Pro Glu Phe Pro Thr Pro Leu Val Ser Lys Ser Pro Asn
Arg 325 330 335Thr Asp Leu
Asp Ile His Ile Asn Gly Gln Ser Ile Asp Asn Phe Gln 340
345 350Ile Ser Glu Thr Gly Leu Thr
35531927DNAH. sapiensCDS(105)...(1908)K+Hnov4 3ggagccccgc agcgcttctt
atgatcagct cggtgtgtgt ctcctcctac cgcgggcgca 60agtcggggaa caagcctccg
tccaaaacat gtctgaagga ggag atg gcc aag ggc 116Met Ala Lys Gly1gag gcg
tcg gag aag atc atc atc aac gtg ggc ggc acg cga cat gag 164Glu Ala
Ser Glu Lys Ile Ile Ile Asn Val Gly Gly Thr Arg His Glu5
10 15 20acc tac cgc agc acc ctg cgc
acc cta ccg gga acc cgc ctc gcc tgg 212Thr Tyr Arg Ser Thr Leu Arg
Thr Leu Pro Gly Thr Arg Leu Ala Trp 25 30
35ctg gcc gac ccc gac ggc ggg ggc cgg ccc gag acc gat
ggc ggc ggt 260Leu Ala Asp Pro Asp Gly Gly Gly Arg Pro Glu Thr Asp
Gly Gly Gly 40 45 50gtg ggt
agc agc ggc agc agc ggc ggc ggg ggc tgc gag ttc ttc ttc 308Val Gly
Ser Ser Gly Ser Ser Gly Gly Gly Gly Cys Glu Phe Phe Phe 55
60 65gac agg cac ccg ggc gtc ttc gcc tac gtg
ctc aac tac tac cgc acc 356Asp Arg His Pro Gly Val Phe Ala Tyr Val
Leu Asn Tyr Tyr Arg Thr 70 75 80ggc
aag ctg cac tgc ccc gca gac gtg tgc ggg ccg ctc ttc gag gag 404Gly
Lys Leu His Cys Pro Ala Asp Val Cys Gly Pro Leu Phe Glu Glu85
90 95 100gag ctg gcc ttc tgg ggc
atc gac gag acc gac gtg gag ccc tgc tgc 452Glu Leu Ala Phe Trp Gly
Ile Asp Glu Thr Asp Val Glu Pro Cys Cys 105
110 115tgg atg acc tac cgg cag cac cgc gac gcc gag gag
gcg ctg gac atc 500Trp Met Thr Tyr Arg Gln His Arg Asp Ala Glu Glu
Ala Leu Asp Ile 120 125 130ttc
gag acc ccc gac ctc att ggc ggc gac ccc ggc gac gac gag gac 548Phe
Glu Thr Pro Asp Leu Ile Gly Gly Asp Pro Gly Asp Asp Glu Asp 135
140 145ctg gcg gcc aag agg ctg ggc atc gag
gac gcg gcg ggg ctc ggg ggc 596Leu Ala Ala Lys Arg Leu Gly Ile Glu
Asp Ala Ala Gly Leu Gly Gly 150 155
160ccc gac ggc aaa tct ggc cgc tgg agg agg ctg cag ccc cgc atg tgg
644Pro Asp Gly Lys Ser Gly Arg Trp Arg Arg Leu Gln Pro Arg Met Trp165
170 175 180gcc ctc ttc gaa
gac ccc tac tcg tcc aga gcc gcc agg ttt att gct 692Ala Leu Phe Glu
Asp Pro Tyr Ser Ser Arg Ala Ala Arg Phe Ile Ala 185
190 195ttt gct tct tta ttc ttc atc ctg gtt tca
att aca act ttt tgc ctg 740Phe Ala Ser Leu Phe Phe Ile Leu Val Ser
Ile Thr Thr Phe Cys Leu 200 205
210gaa aca cat gaa gct ttc aat att gtt aaa aac aag aca gaa cca gtc
788Glu Thr His Glu Ala Phe Asn Ile Val Lys Asn Lys Thr Glu Pro Val
215 220 225atc aat ggc aca agt gtt gtt
cta cag tat gaa att gaa acg gat cct 836Ile Asn Gly Thr Ser Val Val
Leu Gln Tyr Glu Ile Glu Thr Asp Pro 230 235
240gcc ttg acg tat gta gaa gga gtg tgt gtg gtg tgg ttt act ttt gaa
884Ala Leu Thr Tyr Val Glu Gly Val Cys Val Val Trp Phe Thr Phe Glu245
250 255 260ttt tta gtc cgt
att gtt ttt tca ccc aat aaa ctt gaa ttc atc aaa 932Phe Leu Val Arg
Ile Val Phe Ser Pro Asn Lys Leu Glu Phe Ile Lys 265
270 275aat ctc ttg aat atc att gac ttt gtg gcc
atc cta cct ttc tac tta 980Asn Leu Leu Asn Ile Ile Asp Phe Val Ala
Ile Leu Pro Phe Tyr Leu 280 285
290gag gtg gga ctc agt ggg ctg tca tcc aaa gct gct aaa gat gtg ctt
1028Glu Val Gly Leu Ser Gly Leu Ser Ser Lys Ala Ala Lys Asp Val Leu
295 300 305ggc ttc ctc agg gtg gta agg
ttt gtg agg atc ctg aga att ttc aag 1076Gly Phe Leu Arg Val Val Arg
Phe Val Arg Ile Leu Arg Ile Phe Lys 310 315
320ctc acc cgc cat ttt gta ggt ctg agg gtg ctt gga cat act ctt cga
1124Leu Thr Arg His Phe Val Gly Leu Arg Val Leu Gly His Thr Leu Arg325
330 335 340gct agt act aat
gaa ttt ttg ctg ctg ata att ttc ctg gct cta gga 1172Ala Ser Thr Asn
Glu Phe Leu Leu Leu Ile Ile Phe Leu Ala Leu Gly 345
350 355gtt ttg ata ttt gct acc atg atc tac tat
gcc gag aga gtg gga gct 1220Val Leu Ile Phe Ala Thr Met Ile Tyr Tyr
Ala Glu Arg Val Gly Ala 360 365
370caa cct aac gac cct tca gct agt gag cac aca cag ttc aaa aac att
1268Gln Pro Asn Asp Pro Ser Ala Ser Glu His Thr Gln Phe Lys Asn Ile
375 380 385ccc att ggg ttc tgg tgg gct
gta gtg acc atg act acc ctg ggt tat 1316Pro Ile Gly Phe Trp Trp Ala
Val Val Thr Met Thr Thr Leu Gly Tyr 390 395
400ggg gat atg tac ccc caa aca tgg tca ggc atg ctg gtg gga gcc ctg
1364Gly Asp Met Tyr Pro Gln Thr Trp Ser Gly Met Leu Val Gly Ala Leu405
410 415 420tgt gct ctg gct
gga gtg ctg aca ata gcc atg cca gtg cct gtc att 1412Cys Ala Leu Ala
Gly Val Leu Thr Ile Ala Met Pro Val Pro Val Ile 425
430 435gtc aat aat ttt gga atg tac tac tcc ttg
gca atg gca aag cag aaa 1460Val Asn Asn Phe Gly Met Tyr Tyr Ser Leu
Ala Met Ala Lys Gln Lys 440 445
450ctt cca agg aaa aga aag aag cac atc cct cct gct cct cag gca agc
1508Leu Pro Arg Lys Arg Lys Lys His Ile Pro Pro Ala Pro Gln Ala Ser
455 460 465tca cct act ttt tgc aag aca
gaa tta aat atg gcc tgc aat agt aca 1556Ser Pro Thr Phe Cys Lys Thr
Glu Leu Asn Met Ala Cys Asn Ser Thr 470 475
480cag agt gac aca tgt ctg ggc aaa gac aat cga ctt ctg gaa cat aac
1604Gln Ser Asp Thr Cys Leu Gly Lys Asp Asn Arg Leu Leu Glu His Asn485
490 495 500aga tca gtg tta
tca ggt gac gac agt aca gga agt gag ccg cca cta 1652Arg Ser Val Leu
Ser Gly Asp Asp Ser Thr Gly Ser Glu Pro Pro Leu 505
510 515tca ccc cca gaa agg ctc ccc atc aga cgc
tct agt acc aga gac aaa 1700Ser Pro Pro Glu Arg Leu Pro Ile Arg Arg
Ser Ser Thr Arg Asp Lys 520 525
530aac aga aga ggg gaa aca tgt ttc cta ctg acg aca ggt gat tac acg
1748Asn Arg Arg Gly Glu Thr Cys Phe Leu Leu Thr Thr Gly Asp Tyr Thr
535 540 545tgt gct tct gat gga ggg atc
agg aaa gga tat gaa aaa tcc cga agc 1796Cys Ala Ser Asp Gly Gly Ile
Arg Lys Gly Tyr Glu Lys Ser Arg Ser 550 555
560tta aac aac ata gcg ggc ttg gca ggc aat gct ctg agg ctc tct cca
1844Leu Asn Asn Ile Ala Gly Leu Ala Gly Asn Ala Leu Arg Leu Ser Pro565
570 575 580gta aca tca ccc
tac aac tct cct tgt cct ctg agg cgc tct cga tct 1892Val Thr Ser Pro
Tyr Asn Ser Pro Cys Pro Leu Arg Arg Ser Arg Ser 585
590 595ccc atc cca tct atc t tgtaaaccaa
accctcgtg 1927Pro Ile Pro Ser Ile
6004601PRTH. sapiens 4Met Ala Lys Gly Glu Ala Ser Glu Lys Ile Ile Ile Asn
Val Gly Gly1 5 10 15Thr
Arg His Glu Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro Gly Thr 20
25 30Arg Leu Ala Trp Leu Ala Asp Pro
Asp Gly Gly Gly Arg Pro Glu Thr 35 40
45Asp Gly Gly Gly Val Gly Ser Ser Gly Ser Ser Gly Gly Gly Gly Cys
50 55 60Glu Phe Phe Phe Asp Arg His Pro
Gly Val Phe Ala Tyr Val Leu Asn65 70 75
80Tyr Tyr Arg Thr Gly Lys Leu His Cys Pro Ala Asp Val
Cys Gly Pro 85 90 95Leu
Phe Glu Glu Glu Leu Ala Phe Trp Gly Ile Asp Glu Thr Asp Val
100 105 110Glu Pro Cys Cys Trp Met Thr
Tyr Arg Gln His Arg Asp Ala Glu Glu 115 120
125Ala Leu Asp Ile Phe Glu Thr Pro Asp Leu Ile Gly Gly Asp Pro
Gly 130 135 140Asp Asp Glu Asp Leu Ala
Ala Lys Arg Leu Gly Ile Glu Asp Ala Ala145 150
155 160Gly Leu Gly Gly Pro Asp Gly Lys Ser Gly Arg
Trp Arg Arg Leu Gln 165 170
175Pro Arg Met Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg Ala Ala
180 185 190Arg Phe Ile Ala Phe Ala
Ser Leu Phe Phe Ile Leu Val Ser Ile Thr 195 200
205Thr Phe Cys Leu Glu Thr His Glu Ala Phe Asn Ile Val Lys
Asn Lys 210 215 220Thr Glu Pro Val Ile
Asn Gly Thr Ser Val Val Leu Gln Tyr Glu Ile225 230
235 240Glu Thr Asp Pro Ala Leu Thr Tyr Val Glu
Gly Val Cys Val Val Trp 245 250
255Phe Thr Phe Glu Phe Leu Val Arg Ile Val Phe Ser Pro Asn Lys Leu
260 265 270Glu Phe Ile Lys Asn
Leu Leu Asn Ile Ile Asp Phe Val Ala Ile Leu 275
280 285Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser
Ser Lys Ala Ala 290 295 300Lys Asp Val
Leu Gly Phe Leu Arg Val Val Arg Phe Val Arg Ile Leu305
310 315 320Arg Ile Phe Lys Leu Thr Arg
His Phe Val Gly Leu Arg Val Leu Gly 325
330 335His Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu
Leu Ile Ile Phe 340 345 350Leu
Ala Leu Gly Val Leu Ile Phe Ala Thr Met Ile Tyr Tyr Ala Glu 355
360 365Arg Val Gly Ala Gln Pro Asn Asp Pro
Ser Ala Ser Glu His Thr Gln 370 375
380Phe Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala Val Val Thr Met Thr385
390 395 400Thr Leu Gly Tyr
Gly Asp Met Tyr Pro Gln Thr Trp Ser Gly Met Leu 405
410 415Val Gly Ala Leu Cys Ala Leu Ala Gly Val
Leu Thr Ile Ala Met Pro 420 425
430Val Pro Val Ile Val Asn Asn Phe Gly Met Tyr Tyr Ser Leu Ala Met
435 440 445Ala Lys Gln Lys Leu Pro Arg
Lys Arg Lys Lys His Ile Pro Pro Ala 450 455
460Pro Gln Ala Ser Ser Pro Thr Phe Cys Lys Thr Glu Leu Asn Met
Ala465 470 475 480Cys Asn
Ser Thr Gln Ser Asp Thr Cys Leu Gly Lys Asp Asn Arg Leu
485 490 495Leu Glu His Asn Arg Ser Val
Leu Ser Gly Asp Asp Ser Thr Gly Ser 500 505
510Glu Pro Pro Leu Ser Pro Pro Glu Arg Leu Pro Ile Arg Arg
Ser Ser 515 520 525Thr Arg Asp Lys
Asn Arg Arg Gly Glu Thr Cys Phe Leu Leu Thr Thr 530
535 540Gly Asp Tyr Thr Cys Ala Ser Asp Gly Gly Ile Arg
Lys Gly Tyr Glu545 550 555
560Lys Ser Arg Ser Leu Asn Asn Ile Ala Gly Leu Ala Gly Asn Ala Leu
565 570 575Arg Leu Ser Pro Val
Thr Ser Pro Tyr Asn Ser Pro Cys Pro Leu Arg 580
585 590Arg Ser Arg Ser Pro Ile Pro Ser Ile 595
60052293DNAH. sapiensCDS(330)...(1800)K+Hnov6 5gggaagagcg
aacccagggc ccttgctctc gtgcagcgct gcgccctggg tggggacggc 60gtgaggcttg
cagcgcaggt gagagtgatt ttccagtgat tgctttggcc tgtacaacca 120gagaacagga
ttcttccctt ctttttggcc accaaatgcc tatgtgcacc acacattcca 180gtgtgctgag
aagggcagag cttcttggat gatgatggac gtcccaccgg gcaggatgaa 240ggcagagcgt
gtggcatctc cacctcaagg gtgcagcctg atcttcctct tctcccttgc 300cagccagcac
tctgccttct gtatccacc atg gtg ttt ggt gag ttt ttc cat 353
Met Val Phe Gly Glu Phe Phe His
1 5cgc cct gga caa gac gag gaa ctt gtc aac ctg aat
gtg ggg ggc ttt 401Arg Pro Gly Gln Asp Glu Glu Leu Val Asn Leu Asn
Val Gly Gly Phe 10 15 20aag cag tct
gtt gac caa agc acc ctc ctg cgg ttt cct cac acc aga 449Lys Gln Ser
Val Asp Gln Ser Thr Leu Leu Arg Phe Pro His Thr Arg25 30
35 40ctg ggg aag ctg ctt act tgc cat
tct gaa gag gcc att ctg gag ctg 497Leu Gly Lys Leu Leu Thr Cys His
Ser Glu Glu Ala Ile Leu Glu Leu 45 50
55tgt gat gat tac agt gtg gcc gat aag gaa tac tac ttt gat
cgg aat 545Cys Asp Asp Tyr Ser Val Ala Asp Lys Glu Tyr Tyr Phe Asp
Arg Asn 60 65 70ccc tcc ttg
ttc aga tat gtt ttg aat ttt tat tac acg ggg aag ctg 593Pro Ser Leu
Phe Arg Tyr Val Leu Asn Phe Tyr Tyr Thr Gly Lys Leu 75
80 85cat gtc atg gag gag ctg tgc gta ttc tca ttc
tgc cag gag atc gag 641His Val Met Glu Glu Leu Cys Val Phe Ser Phe
Cys Gln Glu Ile Glu 90 95 100tac tgg
ggc atc aac gag ctc ttc att gat tct tgc tgc agc aat cgc 689Tyr Trp
Gly Ile Asn Glu Leu Phe Ile Asp Ser Cys Cys Ser Asn Arg105
110 115 120tac cag gaa cgc aag gag gaa
aac cac gag aag gac tgg gac cag aaa 737Tyr Gln Glu Arg Lys Glu Glu
Asn His Glu Lys Asp Trp Asp Gln Lys 125
130 135agc cat gat gtg agt acc gac tcc tcg ttt gaa gag
tcg tct ctg ttt 785Ser His Asp Val Ser Thr Asp Ser Ser Phe Glu Glu
Ser Ser Leu Phe 140 145 150gag
aaa gag ctg gag aag ttt gac aca ctg cga ttt ggt cag ctc cgg 833Glu
Lys Glu Leu Glu Lys Phe Asp Thr Leu Arg Phe Gly Gln Leu Arg 155
160 165aag aaa atc tgg att aga atg gag aat
cca gcg tac tgc ctg tcc gct 881Lys Lys Ile Trp Ile Arg Met Glu Asn
Pro Ala Tyr Cys Leu Ser Ala 170 175
180aag ctt atc gct atc tcc tcc ttg agc gtg gtg ctg gcc tcc atc gtg
929Lys Leu Ile Ala Ile Ser Ser Leu Ser Val Val Leu Ala Ser Ile Val185
190 195 200gcc atg tgc gtt
cac agc atg tcg gag ttc cag aat gag gat gga gaa 977Ala Met Cys Val
His Ser Met Ser Glu Phe Gln Asn Glu Asp Gly Glu 205
210 215gtg gat gat ccg gtg ctg gaa gga gtg gag
atc gcg tgc att gcc tgg 1025Val Asp Asp Pro Val Leu Glu Gly Val Glu
Ile Ala Cys Ile Ala Trp 220 225
230ttc acc ggg gag ctt gcc gtc cgg ctg gct gcc gct cct tgt caa aag
1073Phe Thr Gly Glu Leu Ala Val Arg Leu Ala Ala Ala Pro Cys Gln Lys
235 240 245aaa ttc tgg aaa aac cct ctg
aac atc att gac ttt gtc tct att att 1121Lys Phe Trp Lys Asn Pro Leu
Asn Ile Ile Asp Phe Val Ser Ile Ile 250 255
260ccc ttc tat gcc acg ttg gct gta gac acc aag gag gaa gag agt gag
1169Pro Phe Tyr Ala Thr Leu Ala Val Asp Thr Lys Glu Glu Glu Ser Glu265
270 275 280gat att gag aac
atg ggc aag gtg gtc cag atc cta cgg ctt atg agg 1217Asp Ile Glu Asn
Met Gly Lys Val Val Gln Ile Leu Arg Leu Met Arg 285
290 295att ttc cga att cta aag ctt gcc cgg cac
tcg gta gga ctt cgg tct 1265Ile Phe Arg Ile Leu Lys Leu Ala Arg His
Ser Val Gly Leu Arg Ser 300 305
310cta ggt gcc aca ctg aga cac agc tac cat gaa gtt ggg ctt ctg ctt
1313Leu Gly Ala Thr Leu Arg His Ser Tyr His Glu Val Gly Leu Leu Leu
315 320 325ctc ttc ctc tct gtg ggc att
tcc att ttc tct gtg ctt atc tac tcc 1361Leu Phe Leu Ser Val Gly Ile
Ser Ile Phe Ser Val Leu Ile Tyr Ser 330 335
340gtg gag aaa gat gac cac aca tcc agc ctc acc agc atc ccc atc tgc
1409Val Glu Lys Asp Asp His Thr Ser Ser Leu Thr Ser Ile Pro Ile Cys345
350 355 360tgg tgg tgg gcc
acc atc agc atg aca act gtg ggc tat gga gac acc 1457Trp Trp Trp Ala
Thr Ile Ser Met Thr Thr Val Gly Tyr Gly Asp Thr 365
370 375cac ccg gtc acc ttg gcg gga aag ctc atc
gcc agc aca tgc atc atc 1505His Pro Val Thr Leu Ala Gly Lys Leu Ile
Ala Ser Thr Cys Ile Ile 380 385
390tgt ggc atc ttg gtg gtg gcc ctt ccc atc acc atc atc ttc aac aag
1553Cys Gly Ile Leu Val Val Ala Leu Pro Ile Thr Ile Ile Phe Asn Lys
395 400 405ttt tcc aag tac tac cag aag
caa aag gac att gat gtg gac cag tgc 1601Phe Ser Lys Tyr Tyr Gln Lys
Gln Lys Asp Ile Asp Val Asp Gln Cys 410 415
420agt gag gat gca cca gag aag tgt cat gag cta cct tac ttt aac att
1649Ser Glu Asp Ala Pro Glu Lys Cys His Glu Leu Pro Tyr Phe Asn Ile425
430 435 440agg gat ata tat
gca cag cgg atg cac gcc ttc att acc agt ctc tct 1697Arg Asp Ile Tyr
Ala Gln Arg Met His Ala Phe Ile Thr Ser Leu Ser 445
450 455tct gta ggc att gtg gtg agc gat cct gac
tcc aca gat gct tca agc 1745Ser Val Gly Ile Val Val Ser Asp Pro Asp
Ser Thr Asp Ala Ser Ser 460 465
470att gaa gac aat gag gac att tgt aac acc acc tcc ttg gag aat tgc
1793Ile Glu Asp Asn Glu Asp Ile Cys Asn Thr Thr Ser Leu Glu Asn Cys
475 480 485aca gca a aatgagcggg
ggtgtttgtg cctgtttctc ttatcctttc ccaacattag 1850Thr Ala
490gttaacacag ctttataaac ctcagtgggt tcgttaaaat catttaattc tcagggtgta
1910cctttcagcc atagttggac attcattgct gaattctgaa atgatagaat tgtctttatt
1970tttctctgtg aggtcaatta aatgccttgt tctgaaattt attttttaca agagagagtt
2030gtgatagagt ttggaatata agataaatgg tattgggtgg ggtttgtggc tacagcttat
2090gcatcattct gtgtttgtca tttactcaca ttgagctaac tttaaattac tgacaagtag
2150aatcaaaggt gcagctgact gagacgacat gcatgtaaga tccacaaaat gagacaatgc
2210atgtaaatcc atgctcatgt tctaaacatg gaaactagga gcctaataaa cttcctaatt
2270cagaaaaaaa aaaaaaaaaa aaa
22936490PRTH. sapiens 6Met Val Phe Gly Glu Phe Phe His Arg Pro Gly Gln
Asp Glu Glu Leu1 5 10
15Val Asn Leu Asn Val Gly Gly Phe Lys Gln Ser Val Asp Gln Ser Thr
20 25 30Leu Leu Arg Phe Pro His Thr
Arg Leu Gly Lys Leu Leu Thr Cys His 35 40
45Ser Glu Glu Ala Ile Leu Glu Leu Cys Asp Asp Tyr Ser Val Ala
Asp 50 55 60Lys Glu Tyr Tyr Phe Asp
Arg Asn Pro Ser Leu Phe Arg Tyr Val Leu65 70
75 80Asn Phe Tyr Tyr Thr Gly Lys Leu His Val Met
Glu Glu Leu Cys Val 85 90
95Phe Ser Phe Cys Gln Glu Ile Glu Tyr Trp Gly Ile Asn Glu Leu Phe
100 105 110Ile Asp Ser Cys Cys Ser
Asn Arg Tyr Gln Glu Arg Lys Glu Glu Asn 115 120
125His Glu Lys Asp Trp Asp Gln Lys Ser His Asp Val Ser Thr
Asp Ser 130 135 140Ser Phe Glu Glu Ser
Ser Leu Phe Glu Lys Glu Leu Glu Lys Phe Asp145 150
155 160Thr Leu Arg Phe Gly Gln Leu Arg Lys Lys
Ile Trp Ile Arg Met Glu 165 170
175Asn Pro Ala Tyr Cys Leu Ser Ala Lys Leu Ile Ala Ile Ser Ser Leu
180 185 190Ser Val Val Leu Ala
Ser Ile Val Ala Met Cys Val His Ser Met Ser 195
200 205Glu Phe Gln Asn Glu Asp Gly Glu Val Asp Asp Pro
Val Leu Glu Gly 210 215 220Val Glu Ile
Ala Cys Ile Ala Trp Phe Thr Gly Glu Leu Ala Val Arg225
230 235 240Leu Ala Ala Ala Pro Cys Gln
Lys Lys Phe Trp Lys Asn Pro Leu Asn 245
250 255Ile Ile Asp Phe Val Ser Ile Ile Pro Phe Tyr Ala
Thr Leu Ala Val 260 265 270Asp
Thr Lys Glu Glu Glu Ser Glu Asp Ile Glu Asn Met Gly Lys Val 275
280 285Val Gln Ile Leu Arg Leu Met Arg Ile
Phe Arg Ile Leu Lys Leu Ala 290 295
300Arg His Ser Val Gly Leu Arg Ser Leu Gly Ala Thr Leu Arg His Ser305
310 315 320Tyr His Glu Val
Gly Leu Leu Leu Leu Phe Leu Ser Val Gly Ile Ser 325
330 335Ile Phe Ser Val Leu Ile Tyr Ser Val Glu
Lys Asp Asp His Thr Ser 340 345
350Ser Leu Thr Ser Ile Pro Ile Cys Trp Trp Trp Ala Thr Ile Ser Met
355 360 365Thr Thr Val Gly Tyr Gly Asp
Thr His Pro Val Thr Leu Ala Gly Lys 370 375
380Leu Ile Ala Ser Thr Cys Ile Ile Cys Gly Ile Leu Val Val Ala
Leu385 390 395 400Pro Ile
Thr Ile Ile Phe Asn Lys Phe Ser Lys Tyr Tyr Gln Lys Gln
405 410 415Lys Asp Ile Asp Val Asp Gln
Cys Ser Glu Asp Ala Pro Glu Lys Cys 420 425
430His Glu Leu Pro Tyr Phe Asn Ile Arg Asp Ile Tyr Ala Gln
Arg Met 435 440 445His Ala Phe Ile
Thr Ser Leu Ser Ser Val Gly Ile Val Val Ser Asp 450
455 460Pro Asp Ser Thr Asp Ala Ser Ser Ile Glu Asp Asn
Glu Asp Ile Cys465 470 475
480Asn Thr Thr Ser Leu Glu Asn Cys Thr Ala 485
49073080DNAH. sapiensCDS(480)...(1977)K+Hnov9 7gtctctcctc ttcctcctcc
tccgccccac atctccctcc ttcctccctt ccccaacccc 60tccacccacc aagtagcgag
tcattcaatc tgtacacctc ctgggctggg aatcgcaatt 120gcgaagttgg gaggcggggt
gacaacgttt gggaagggcc agggcgaccg gcagtgtgca 180cagggactgt gtcgggcttg
gacctcacct gatcctctct cttagcgcga cccttcctct 240gctccctgtc tcctctttct
gccacttgtg cgctgcttcc gcgcactccc ggctccctag 300cggcaggagg aggaaggcgc
acagcgggtg gagagggtgc gccaaggaga ggtaacccct 360tcgggagccc ggggaatccc
ggccgccacc aggggccgtg ccaccgccct cgcgggacca 420aagcttccgg cgtgtcccca
actttgtggc gccctcaggc cgcggcgact gggttagag 479atg cct tcc agc ggc aga
gcg ctg ctg gac tcg ccg ctg gac agc ggc 527Met Pro Ser Ser Gly Arg
Ala Leu Leu Asp Ser Pro Leu Asp Ser Gly1 5
10 15tcc ctg acc tcc ctg gac tct agt gtc ttc tgc agc
gag ggt gaa ggg 575Ser Leu Thr Ser Leu Asp Ser Ser Val Phe Cys Ser
Glu Gly Glu Gly 20 25 30gag
ccc ttg gcg ctc ggg gac tgc ttc acg gtc aac gtg ggc ggc agc 623Glu
Pro Leu Ala Leu Gly Asp Cys Phe Thr Val Asn Val Gly Gly Ser 35
40 45cgc ttc gtg ctc tcg cag cag gcg ctg
tcc tgc ttc ccg cac acg cgc 671Arg Phe Val Leu Ser Gln Gln Ala Leu
Ser Cys Phe Pro His Thr Arg 50 55
60ctt ggc aag ctg gcc gtg gtg gtg gct tcc tac cgc cgc ccc ggg gcc
719Leu Gly Lys Leu Ala Val Val Val Ala Ser Tyr Arg Arg Pro Gly Ala65
70 75 80ctg gcc gcc gtg ccc
agc cct ctg gag ctt tgc gac gat gcc aac ccc 767Leu Ala Ala Val Pro
Ser Pro Leu Glu Leu Cys Asp Asp Ala Asn Pro 85
90 95gtg gac aac gag tac ttc ttc gac cgc agc tcg
cag gcg ttc cga tat 815Val Asp Asn Glu Tyr Phe Phe Asp Arg Ser Ser
Gln Ala Phe Arg Tyr 100 105
110gtc ctg cac tac tac cgc acc ggc cgc ctg cat gtc atg gag cag ctg
863Val Leu His Tyr Tyr Arg Thr Gly Arg Leu His Val Met Glu Gln Leu
115 120 125tgc gcg ctc tcc ttc ctg cag
gag atc cag tac tgg ggc atc gat gag 911Cys Ala Leu Ser Phe Leu Gln
Glu Ile Gln Tyr Trp Gly Ile Asp Glu 130 135
140ctc agc atc gat tcc tgc tgc agg gac aga tac ttc aga agg aaa gag
959Leu Ser Ile Asp Ser Cys Cys Arg Asp Arg Tyr Phe Arg Arg Lys Glu145
150 155 160ctg agt gaa act
tta gac ttc aag aag gac aca gaa gac cag gaa agt 1007Leu Ser Glu Thr
Leu Asp Phe Lys Lys Asp Thr Glu Asp Gln Glu Ser 165
170 175caa cat gag agt gaa cag gac ttc tcc caa
gga cct tgt ccc act gtt 1055Gln His Glu Ser Glu Gln Asp Phe Ser Gln
Gly Pro Cys Pro Thr Val 180 185
190cgc cag aag ctc tgg aat atc ctg gag aaa cct gga tct tcc aca gct
1103Arg Gln Lys Leu Trp Asn Ile Leu Glu Lys Pro Gly Ser Ser Thr Ala
195 200 205gcc cgt atc ttt ggc gtc atc
tcc att atc ttc gtg gtg gtg tcc atc 1151Ala Arg Ile Phe Gly Val Ile
Ser Ile Ile Phe Val Val Val Ser Ile 210 215
220att aac atg gcc ctg atg tca gct gag tta agc tgg ctg gac ctg cag
1199Ile Asn Met Ala Leu Met Ser Ala Glu Leu Ser Trp Leu Asp Leu Gln225
230 235 240ctg ctg gaa atc
ctg gag tat gtg tgc att agc tgg ttc acc ggg gag 1247Leu Leu Glu Ile
Leu Glu Tyr Val Cys Ile Ser Trp Phe Thr Gly Glu 245
250 255ttt gtc ctc cgc ttc ctg tgt gtg cgg gac
agg tgt cgc ttc cta aga 1295Phe Val Leu Arg Phe Leu Cys Val Arg Asp
Arg Cys Arg Phe Leu Arg 260 265
270aag gtg cca aac atc ata gac ctc ctt gcc atc ttg ccc ttc tac atc
1343Lys Val Pro Asn Ile Ile Asp Leu Leu Ala Ile Leu Pro Phe Tyr Ile
275 280 285act ctt ctg gta gag agc cta
agt ggg agc cag acc acg cag gag ctg 1391Thr Leu Leu Val Glu Ser Leu
Ser Gly Ser Gln Thr Thr Gln Glu Leu 290 295
300gag aac gtg ggg cgc att gtc cag gtg ttg agg ctg ctc agg gct ctg
1439Glu Asn Val Gly Arg Ile Val Gln Val Leu Arg Leu Leu Arg Ala Leu305
310 315 320cgc atg cta aag
ctg ggc aga cat tcc aca gga tta cgc tcc ctt ggg 1487Arg Met Leu Lys
Leu Gly Arg His Ser Thr Gly Leu Arg Ser Leu Gly 325
330 335atg aca atc acc cag tgt tac gaa gaa gtc
ggc cta ctg ctc cta ttt 1535Met Thr Ile Thr Gln Cys Tyr Glu Glu Val
Gly Leu Leu Leu Leu Phe 340 345
350cta tcc gtg gga atc tct ata ttt tca act gta gaa tac ttt gct gag
1583Leu Ser Val Gly Ile Ser Ile Phe Ser Thr Val Glu Tyr Phe Ala Glu
355 360 365caa agc att cct gac aca acc
ttc aca agt gtc cct tgt gca tgg tgg 1631Gln Ser Ile Pro Asp Thr Thr
Phe Thr Ser Val Pro Cys Ala Trp Trp 370 375
380tgg gcc acc acc tct atg act act gtg gga tat ggg gac att aga cca
1679Trp Ala Thr Thr Ser Met Thr Thr Val Gly Tyr Gly Asp Ile Arg Pro385
390 395 400gac acc acc aca
ggc aaa atc gtg gcc ttc atg tgt ata tta tcg gga 1727Asp Thr Thr Thr
Gly Lys Ile Val Ala Phe Met Cys Ile Leu Ser Gly 405
410 415att ctt gtc ttg gcc ttg cct att gct att
att aac gat cgc ttc tct 1775Ile Leu Val Leu Ala Leu Pro Ile Ala Ile
Ile Asn Asp Arg Phe Ser 420 425
430gct tgc tac ttc acc ttg aaa ctc aag gaa gca gct gtt aga cag cgt
1823Ala Cys Tyr Phe Thr Leu Lys Leu Lys Glu Ala Ala Val Arg Gln Arg
435 440 445gaa gcc cta aag aag ctt acc
aag aat ata gcc act gac tca tat atc 1871Glu Ala Leu Lys Lys Leu Thr
Lys Asn Ile Ala Thr Asp Ser Tyr Ile 450 455
460agt gtt aac ttg aga gat gtc tat gcc cgg agt atc atg gag atg ctg
1919Ser Val Asn Leu Arg Asp Val Tyr Ala Arg Ser Ile Met Glu Met Leu465
470 475 480cga ctg aaa ggc
aga gaa aga gca agt act agg agc agc ggg gga gat 1967Arg Leu Lys Gly
Arg Glu Arg Ala Ser Thr Arg Ser Ser Gly Gly Asp 485
490 495gat ttc tgg t tttgaattaa ttttcaattt
atttacaaaa gctatgtaca 2017Asp Phe Trpattaactaaa atgataaagc
agtgatgtgg atttctgtat tctgatgatg agtctcttca 2077gagtactgct catcttaatt
aatttttgct gatatattgc ttcatctact agaatatttc 2137acatcaccta taacaactgc
acagtgttct gacacatttg agtgtccaaa atagccaatt 2197aacacaacca aatacaactg
ggccaatata aacatgtttg aattgtcaaa tataaaataa 2257tgttattgca atacatacaa
aaaagttaaa gattttatgt atcactaaca ttagaagttt 2317tttgcaccac taatttttta
aaaatggaag gtaaactgca tagcccagag aaagataagt 2377aaatatttaa gaacatattg
aacaactttg ctatttaaag atattatcca agtacataaa 2437ttactccgtt ctctatcagt
taaagctatt gaatataata cttagcttta caagagaaaa 2497cccatatttg atgggcagag
attatatccc tatcttcttt ttcatgtaaa ccactggtca 2557caaatgaact gatctctgta
tcccattatt actataagag gtgggaatcc caaaactgct 2617tagattgcag tacatgagtc
tacacaaaga cttcaacaat tgcacatctt cattctccca 2677actgagtgta gtatgtggag
cataaaacag catatttctt agtatttcat gaatatcaga 2737tggtctttaa atgtctcttt
atggatgtat tgttcacatt atggctttaa aataatgaat 2797atgtaaaagt gaggtagtga
acatcctaaa tttctacact ggaattacta aataatctta 2857tttcataaat gggaaatata
tgttaaatga catcactgga tgaacttgaa gatcttttac 2917ttgttaacaa aaaaatacta
tggacagctt tctgattgtt ggggtaaata gcaaatgttc 2977aaactttgca ggcattttga
cattcatcat aacaacacaa ttcctagaca ttgtattata 3037taattaaagc caaaacctct
aaagctaaaa aaaaaaaaaa aaa 30808499PRTH. sapiens 8Met
Pro Ser Ser Gly Arg Ala Leu Leu Asp Ser Pro Leu Asp Ser Gly1
5 10 15Ser Leu Thr Ser Leu Asp Ser Ser
Val Phe Cys Ser Glu Gly Glu Gly 20 25
30Glu Pro Leu Ala Leu Gly Asp Cys Phe Thr Val Asn Val Gly Gly
Ser 35 40 45Arg Phe Val Leu Ser
Gln Gln Ala Leu Ser Cys Phe Pro His Thr Arg 50 55
60Leu Gly Lys Leu Ala Val Val Val Ala Ser Tyr Arg Arg Pro
Gly Ala65 70 75 80Leu
Ala Ala Val Pro Ser Pro Leu Glu Leu Cys Asp Asp Ala Asn Pro
85 90 95Val Asp Asn Glu Tyr Phe Phe
Asp Arg Ser Ser Gln Ala Phe Arg Tyr 100 105
110Val Leu His Tyr Tyr Arg Thr Gly Arg Leu His Val Met Glu
Gln Leu 115 120 125Cys Ala Leu Ser
Phe Leu Gln Glu Ile Gln Tyr Trp Gly Ile Asp Glu 130
135 140Leu Ser Ile Asp Ser Cys Cys Arg Asp Arg Tyr Phe
Arg Arg Lys Glu145 150 155
160Leu Ser Glu Thr Leu Asp Phe Lys Lys Asp Thr Glu Asp Gln Glu Ser
165 170 175Gln His Glu Ser Glu
Gln Asp Phe Ser Gln Gly Pro Cys Pro Thr Val 180
185 190Arg Gln Lys Leu Trp Asn Ile Leu Glu Lys Pro Gly
Ser Ser Thr Ala 195 200 205Ala Arg
Ile Phe Gly Val Ile Ser Ile Ile Phe Val Val Val Ser Ile 210
215 220Ile Asn Met Ala Leu Met Ser Ala Glu Leu Ser
Trp Leu Asp Leu Gln225 230 235
240Leu Leu Glu Ile Leu Glu Tyr Val Cys Ile Ser Trp Phe Thr Gly Glu
245 250 255Phe Val Leu Arg
Phe Leu Cys Val Arg Asp Arg Cys Arg Phe Leu Arg 260
265 270Lys Val Pro Asn Ile Ile Asp Leu Leu Ala Ile
Leu Pro Phe Tyr Ile 275 280 285Thr
Leu Leu Val Glu Ser Leu Ser Gly Ser Gln Thr Thr Gln Glu Leu 290
295 300Glu Asn Val Gly Arg Ile Val Gln Val Leu
Arg Leu Leu Arg Ala Leu305 310 315
320Arg Met Leu Lys Leu Gly Arg His Ser Thr Gly Leu Arg Ser Leu
Gly 325 330 335Met Thr Ile
Thr Gln Cys Tyr Glu Glu Val Gly Leu Leu Leu Leu Phe 340
345 350Leu Ser Val Gly Ile Ser Ile Phe Ser Thr
Val Glu Tyr Phe Ala Glu 355 360
365Gln Ser Ile Pro Asp Thr Thr Phe Thr Ser Val Pro Cys Ala Trp Trp 370
375 380Trp Ala Thr Thr Ser Met Thr Thr
Val Gly Tyr Gly Asp Ile Arg Pro385 390
395 400Asp Thr Thr Thr Gly Lys Ile Val Ala Phe Met Cys
Ile Leu Ser Gly 405 410
415Ile Leu Val Leu Ala Leu Pro Ile Ala Ile Ile Asn Asp Arg Phe Ser
420 425 430Ala Cys Tyr Phe Thr Leu
Lys Leu Lys Glu Ala Ala Val Arg Gln Arg 435 440
445Glu Ala Leu Lys Lys Leu Thr Lys Asn Ile Ala Thr Asp Ser
Tyr Ile 450 455 460Ser Val Asn Leu Arg
Asp Val Tyr Ala Arg Ser Ile Met Glu Met Leu465 470
475 480Arg Leu Lys Gly Arg Glu Arg Ala Ser Thr
Arg Ser Ser Gly Gly Asp 485 490
495Asp Phe Trp 93424DNAH. sapiensCDS(257)...(2195)K+Hnov12
9ctcttctcca tgtccccaag gcccttctca gtccctcaga acattgccca ggcccctcct
60aggttctgta aatgtccccc agactccttc ccatctcttt agttcttcct cctggttcct
120cttggcctct ctagacaccc ccagtttcct tgtttgggtg gctcaaggtg tctccaagcc
180cccaccatcc tggagacagc cacattctcc taaacgccac cctcactaag tctccctggg
240cttggggagt ggcacg atg gcg gca ggc ctg gcc acg tgg ctg cct ttt gct
292Met Ala Ala Gly Leu Ala Thr Trp Leu Pro Phe Ala1 5
10cgg gca gca gca gtg ggc tgg ctg ccc ccg gcc cag caa ccc ctg
ccc 340Arg Ala Ala Ala Val Gly Trp Leu Pro Pro Ala Gln Gln Pro Leu
Pro 15 20 25ccg gca ccg ggg gtg
aag gca tct cga gga gat grg gtt ctg gtg gtg 388Pro Ala Pro Gly Val
Lys Ala Ser Arg Gly Asp Xaa Val Leu Val Val 30 35
40aac gtg agc gga cgg cgc ttt gag act tgg aag aat acg ctg
gac cgc 436Asn Val Ser Gly Arg Arg Phe Glu Thr Trp Lys Asn Thr Leu
Asp Arg45 50 55 60tac
cca gac acc ttg ctg ggc agc tcg gag aag gaa ttc ttc tac gat 484Tyr
Pro Asp Thr Leu Leu Gly Ser Ser Glu Lys Glu Phe Phe Tyr Asp
65 70 75gct gac tca ggc gag tac ttc
ttc gat cgc gac cct gac atg ttc cgc 532Ala Asp Ser Gly Glu Tyr Phe
Phe Asp Arg Asp Pro Asp Met Phe Arg 80 85
90cat gtg ctg aac ttc tac cga acg ggg cgg ctg cat tgc cca
cgg cag 580His Val Leu Asn Phe Tyr Arg Thr Gly Arg Leu His Cys Pro
Arg Gln 95 100 105gag tgc atc cag
gcc ttc gac gaa gag ctg gct ttc tac ggc ctg gtt 628Glu Cys Ile Gln
Ala Phe Asp Glu Glu Leu Ala Phe Tyr Gly Leu Val 110
115 120ccc gag cta gtc ggt gac tgc tgc ctt gaa gag tat
cgg gac cga aag 676Pro Glu Leu Val Gly Asp Cys Cys Leu Glu Glu Tyr
Arg Asp Arg Lys125 130 135
140aag gag aat gcc gag cgc ctg gca gag gat gag gag gca gag cag gcc
724Lys Glu Asn Ala Glu Arg Leu Ala Glu Asp Glu Glu Ala Glu Gln Ala
145 150 155ggg gac ggc cca gcc
ctg cca gca ggc agc tcc ctg cgg cag cgg ctc 772Gly Asp Gly Pro Ala
Leu Pro Ala Gly Ser Ser Leu Arg Gln Arg Leu 160
165 170tgg cgg gcc ttc gag aat cca cac acg agc acc gca
gcc ctc gtt ttc 820Trp Arg Ala Phe Glu Asn Pro His Thr Ser Thr Ala
Ala Leu Val Phe 175 180 185tac tat
gtg acc ggc ttc ttc atc gcc gtg tcg gtc atc gcc aat gtg 868Tyr Tyr
Val Thr Gly Phe Phe Ile Ala Val Ser Val Ile Ala Asn Val 190
195 200gtg gag acc atc cca tgc cgc ggc tct gca cgc
agg tcc tca agg gag 916Val Glu Thr Ile Pro Cys Arg Gly Ser Ala Arg
Arg Ser Ser Arg Glu205 210 215
220cag ccc tgt ggc gaa cgc ttc cca cag gcc ttt ttc tgc atg gac aca
964Gln Pro Cys Gly Glu Arg Phe Pro Gln Ala Phe Phe Cys Met Asp Thr
225 230 235gcc tgt gta ctc ata
ttc aca ggt gaa tac ctc ctg cgg ctg ttt gcc 1012Ala Cys Val Leu Ile
Phe Thr Gly Glu Tyr Leu Leu Arg Leu Phe Ala 240
245 250gcc ccc agc cgt tgc cgc ttc ctg cgg agt gtc atg
agc ctc atc gac 1060Ala Pro Ser Arg Cys Arg Phe Leu Arg Ser Val Met
Ser Leu Ile Asp 255 260 265gtg gtg
gcc atc ctg ccc tac tac att ggg ctt ttg gtg ccc aag aac 1108Val Val
Ala Ile Leu Pro Tyr Tyr Ile Gly Leu Leu Val Pro Lys Asn 270
275 280gac gat gtc tct ggc gcc ttt gtc acc ctg cgt
gtg ttc cgg gtg ttt 1156Asp Asp Val Ser Gly Ala Phe Val Thr Leu Arg
Val Phe Arg Val Phe285 290 295
300cgc atc ttc aag ttc tcc agg cac tca cag ggc ttg agg att ctg ggc
1204Arg Ile Phe Lys Phe Ser Arg His Ser Gln Gly Leu Arg Ile Leu Gly
305 310 315tac aca ctc aag agc
tgt gcc tct gag ctg ggc ttt ctc ctc ttt tcc 1252Tyr Thr Leu Lys Ser
Cys Ala Ser Glu Leu Gly Phe Leu Leu Phe Ser 320
325 330cta acc atg gcc atc atc atc ttt gcc act gtc atg
ttt tat gct gag 1300Leu Thr Met Ala Ile Ile Ile Phe Ala Thr Val Met
Phe Tyr Ala Glu 335 340 345aag ggc
aca aac aag acc aac ttt aca agc atc cct gcg gcc ttc tgg 1348Lys Gly
Thr Asn Lys Thr Asn Phe Thr Ser Ile Pro Ala Ala Phe Trp 350
355 360tat acc att gtc acc atg acc acg ctt ggc tac
gga gac atg gtg ccc 1396Tyr Thr Ile Val Thr Met Thr Thr Leu Gly Tyr
Gly Asp Met Val Pro365 370 375
380agc acc att gct ggc aag att ttc ggg tcc atc tgc tca ctc agt ggc
1444Ser Thr Ile Ala Gly Lys Ile Phe Gly Ser Ile Cys Ser Leu Ser Gly
385 390 395gtc ttg gtc att gcc
ctg cct gtg cca gtc att gtg tcc aac ttt agc 1492Val Leu Val Ile Ala
Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser 400
405 410cgc atc tac cac cag aac cag cgg gct gac aag cgc
cga gca cag cag 1540Arg Ile Tyr His Gln Asn Gln Arg Ala Asp Lys Arg
Arg Ala Gln Gln 415 420 425aag gtg
cgc ttg gca agg atc cga ttg gca aag agt ggt acc acc aat 1588Lys Val
Arg Leu Ala Arg Ile Arg Leu Ala Lys Ser Gly Thr Thr Asn 430
435 440gcc ttc ctg cag tac aag cag aat ggg ggc ctt
gag gac agc ggc agt 1636Ala Phe Leu Gln Tyr Lys Gln Asn Gly Gly Leu
Glu Asp Ser Gly Ser445 450 455
460ggc gag gaa cag gct ctt tgt gtc agg aac cgt tct gcc ttt gaa cag
1684Gly Glu Glu Gln Ala Leu Cys Val Arg Asn Arg Ser Ala Phe Glu Gln
465 470 475caa cat cac cac ttg
ctg cac tgt cta gag aag aca acg tgc cat gag 1732Gln His His His Leu
Leu His Cys Leu Glu Lys Thr Thr Cys His Glu 480
485 490ttc aca gat gag ctc acc ttc agt gaa gcc ctg gga
gcc gtc tcg ccg 1780Phe Thr Asp Glu Leu Thr Phe Ser Glu Ala Leu Gly
Ala Val Ser Pro 495 500 505ggt ggc
cgc acc agc cgt agc acc tct gtg tct tcc cag cca gtg gga 1828Gly Gly
Arg Thr Ser Arg Ser Thr Ser Val Ser Ser Gln Pro Val Gly 510
515 520ccc gga agc ctg ctg tct tct tgc tgc cct cgc
agg gcc aag cgc cgc 1876Pro Gly Ser Leu Leu Ser Ser Cys Cys Pro Arg
Arg Ala Lys Arg Arg525 530 535
540gcc atc cgc ctt gcc aac tcc act gcc tca gtc agc cgt ggc agc atg
1924Ala Ile Arg Leu Ala Asn Ser Thr Ala Ser Val Ser Arg Gly Ser Met
545 550 555cag gag ctg gac atg
ctg gca ggg ctg cgc agg agc cat gcc cct cag 1972Gln Glu Leu Asp Met
Leu Ala Gly Leu Arg Arg Ser His Ala Pro Gln 560
565 570agc cgc tcc agc ctc aat gcc aag ccc cat gac agc
ctt gac ctg aac 2020Ser Arg Ser Ser Leu Asn Ala Lys Pro His Asp Ser
Leu Asp Leu Asn 575 580 585tgc gac
agc cgg gac ttc gtg gct gcc att atc agc atc cct acc cct 2068Cys Asp
Ser Arg Asp Phe Val Ala Ala Ile Ile Ser Ile Pro Thr Pro 590
595 600cct gcc aac acc cca gat gag agc caa cct tcc
tcc cct ggc ggc ggt 2116Pro Ala Asn Thr Pro Asp Glu Ser Gln Pro Ser
Ser Pro Gly Gly Gly605 610 615
620ggc agg gcc ggc agc acc ctc agg aac tcc agc ctg ggt acc cct tgc
2164Gly Arg Ala Gly Ser Thr Leu Arg Asn Ser Ser Leu Gly Thr Pro Cys
625 630 635ctc ttc ccc gag act
gtc aag atc tca tcc c tgtgaggggt aggcctgctg 2215Leu Phe Pro Glu Thr
Val Lys Ile Ser Ser 640 645attcagaggg
tcctcttcat ttttgggaac tcctttccaa agccatattt ttgggaggca 2275gagaggggca
ggcttgggca ccccttctgc cccccccact gagaactatg caatggagtt 2335tcatgaaatg
gtccacatag tggggaagta gccaggaaat gagaaacttc ctcccacccc 2395agacattttt
cctggtggga gctgaagcac tgggcttcca caggcccctg gcctccttgc 2455cctagcacac
tgggactggc cccactctcc cagctggact cctgcatgct cctccccttg 2515ggctctcaga
tgaaggcaaa gctttgatcc gacatctgag ctctagccta agaaggagag 2575ttgagatttc
ctcctccctc tggctgggat atggagcttt ggaggttcag agaagagaac 2635cctcacctct
gatctggcct ctacgagagg tcctcatctc catctggccc aacaattccc 2695agattctgaa
gcttggaatg caaacacagg cttcatgggc tgtggcctct gcagcgacct 2755gccatcccca
ggccttgcct gaggggtcag gctgcctctc ccaacacaca ctcagatagc 2815acaaattcta
ccatcccctt ccctggctgc tggaaatgga ccccgcaacc ctgtcctctg 2875ctgggccccc
agcaaactct agcaatagca gctgctgccg tgtcattatg caaagcctct 2935gaccagtttg
ctgcagcatt tacatctgcc ctaatcagag gggccacctc taactcctcc 2995tcctcctctc
ttctcctctg gtttgcgtcc ttcctgggtt gggctggagt ctggactggc 3055tgagataaga
gcctggcaac cagcaagagc tgggctgtat ttggagatca tgggctgatt 3115ccatgttctt
gggcaacagt ccagaagcat caggggctcc ggcctgggat gtttctgaac 3175tttgggagtt
ataggagaca ggaggaactt ctcctcctcc tcctccccta caattccttt 3235tcacatattc
ctttcttctc cctcttgggt gaccttccaa aactctgctc tcaggctgaa 3295atctggcatc
atctcaggtt ccctgtcccc agcactgtcc ccatggagct ggtggctgac 3355aaagatgtag
tttccatcag tcaataaaac ctgagaggag agatgaggaa aaaaaaaaaa 3415aaaaaaaaa
342410646PRTH.
sapiensVARIANT(1)...(646)Xaa = Any Amino Acid 10Met Ala Ala Gly Leu Ala
Thr Trp Leu Pro Phe Ala Arg Ala Ala Ala1 5
10 15Val Gly Trp Leu Pro Pro Ala Gln Gln Pro Leu Pro Pro
Ala Pro Gly 20 25 30Val Lys
Ala Ser Arg Gly Asp Xaa Val Leu Val Val Asn Val Ser Gly 35
40 45Arg Arg Phe Glu Thr Trp Lys Asn Thr Leu
Asp Arg Tyr Pro Asp Thr 50 55 60Leu
Leu Gly Ser Ser Glu Lys Glu Phe Phe Tyr Asp Ala Asp Ser Gly65
70 75 80Glu Tyr Phe Phe Asp Arg
Asp Pro Asp Met Phe Arg His Val Leu Asn 85
90 95Phe Tyr Arg Thr Gly Arg Leu His Cys Pro Arg Gln
Glu Cys Ile Gln 100 105 110Ala
Phe Asp Glu Glu Leu Ala Phe Tyr Gly Leu Val Pro Glu Leu Val 115
120 125Gly Asp Cys Cys Leu Glu Glu Tyr Arg
Asp Arg Lys Lys Glu Asn Ala 130 135
140Glu Arg Leu Ala Glu Asp Glu Glu Ala Glu Gln Ala Gly Asp Gly Pro145
150 155 160Ala Leu Pro Ala
Gly Ser Ser Leu Arg Gln Arg Leu Trp Arg Ala Phe 165
170 175Glu Asn Pro His Thr Ser Thr Ala Ala Leu
Val Phe Tyr Tyr Val Thr 180 185
190Gly Phe Phe Ile Ala Val Ser Val Ile Ala Asn Val Val Glu Thr Ile
195 200 205Pro Cys Arg Gly Ser Ala Arg
Arg Ser Ser Arg Glu Gln Pro Cys Gly 210 215
220Glu Arg Phe Pro Gln Ala Phe Phe Cys Met Asp Thr Ala Cys Val
Leu225 230 235 240Ile Phe
Thr Gly Glu Tyr Leu Leu Arg Leu Phe Ala Ala Pro Ser Arg
245 250 255Cys Arg Phe Leu Arg Ser Val
Met Ser Leu Ile Asp Val Val Ala Ile 260 265
270Leu Pro Tyr Tyr Ile Gly Leu Leu Val Pro Lys Asn Asp Asp
Val Ser 275 280 285Gly Ala Phe Val
Thr Leu Arg Val Phe Arg Val Phe Arg Ile Phe Lys 290
295 300Phe Ser Arg His Ser Gln Gly Leu Arg Ile Leu Gly
Tyr Thr Leu Lys305 310 315
320Ser Cys Ala Ser Glu Leu Gly Phe Leu Leu Phe Ser Leu Thr Met Ala
325 330 335Ile Ile Ile Phe Ala
Thr Val Met Phe Tyr Ala Glu Lys Gly Thr Asn 340
345 350Lys Thr Asn Phe Thr Ser Ile Pro Ala Ala Phe Trp
Tyr Thr Ile Val 355 360 365Thr Met
Thr Thr Leu Gly Tyr Gly Asp Met Val Pro Ser Thr Ile Ala 370
375 380Gly Lys Ile Phe Gly Ser Ile Cys Ser Leu Ser
Gly Val Leu Val Ile385 390 395
400Ala Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser Arg Ile Tyr His
405 410 415Gln Asn Gln Arg
Ala Asp Lys Arg Arg Ala Gln Gln Lys Val Arg Leu 420
425 430Ala Arg Ile Arg Leu Ala Lys Ser Gly Thr Thr
Asn Ala Phe Leu Gln 435 440 445Tyr
Lys Gln Asn Gly Gly Leu Glu Asp Ser Gly Ser Gly Glu Glu Gln 450
455 460Ala Leu Cys Val Arg Asn Arg Ser Ala Phe
Glu Gln Gln His His His465 470 475
480Leu Leu His Cys Leu Glu Lys Thr Thr Cys His Glu Phe Thr Asp
Glu 485 490 495Leu Thr Phe
Ser Glu Ala Leu Gly Ala Val Ser Pro Gly Gly Arg Thr 500
505 510Ser Arg Ser Thr Ser Val Ser Ser Gln Pro
Val Gly Pro Gly Ser Leu 515 520
525Leu Ser Ser Cys Cys Pro Arg Arg Ala Lys Arg Arg Ala Ile Arg Leu 530
535 540Ala Asn Ser Thr Ala Ser Val Ser
Arg Gly Ser Met Gln Glu Leu Asp545 550
555 560Met Leu Ala Gly Leu Arg Arg Ser His Ala Pro Gln
Ser Arg Ser Ser 565 570
575Leu Asn Ala Lys Pro His Asp Ser Leu Asp Leu Asn Cys Asp Ser Arg
580 585 590Asp Phe Val Ala Ala Ile
Ile Ser Ile Pro Thr Pro Pro Ala Asn Thr 595 600
605Pro Asp Glu Ser Gln Pro Ser Ser Pro Gly Gly Gly Gly Arg
Ala Gly 610 615 620Ser Thr Leu Arg Asn
Ser Ser Leu Gly Thr Pro Cys Leu Phe Pro Glu625 630
635 640Thr Val Lys Ile Ser Ser
645111862DNAH. sapiensCDS(383)...(1157)K+Hnov15 11cagctgaatg tggaggcctt
taagagaact tccagctcct gtaaaaaccc agaccagagg 60actactgacc aacatttcag
gctgatcctc cagacctcga agttactctc cttactctcc 120tgactcttaa ttacatcaca
cctgtgtcga cactctctgg gaaaagactg aagaaataat 180cttttcaaga agcagaaagc
tcctgcatac ataggctgat acgccaccta ctgcaaaacc 240gagctgacag cgcaggcgat
gctgccagcg tttccattcc atcaccaggc tggggctgaa 300taaaggcgtg cttgtgtggt
agtgtctctt tttaaaaaat ctcaaagcca agaagaacaa 360gctgaaatag catcttcaaa
aa atg gag cgt aaa ata aac aga aga gaa aaa 412Met Glu Arg Lys Ile Asn
Arg Arg Glu Lys1 5 10gaa aag gag tat gaa
ggg aaa cac aac agc ctg gaa gat act gat caa 460Glu Lys Glu Tyr Glu
Gly Lys His Asn Ser Leu Glu Asp Thr Asp Gln 15
20 25gga aag aac tgc aaa tcc aca ctg atg acc ctc
aac gtt ggt gga tat 508Gly Lys Asn Cys Lys Ser Thr Leu Met Thr Leu
Asn Val Gly Gly Tyr 30 35
40tta tac att act caa aaa caa aca ctg acc aag tac cca gac act ttc
556Leu Tyr Ile Thr Gln Lys Gln Thr Leu Thr Lys Tyr Pro Asp Thr Phe
45 50 55ctt gaa ggt ata gta aat gga aaa
atc ctc tgc ccg ttt gat gct gat 604Leu Glu Gly Ile Val Asn Gly Lys
Ile Leu Cys Pro Phe Asp Ala Asp 60 65
70ggt cat tat ttc ata gac agg gat ggt ctc ctc ttc agg cat gtc cta
652Gly His Tyr Phe Ile Asp Arg Asp Gly Leu Leu Phe Arg His Val Leu75
80 85 90aac ttc cta cga aat
gga gaa ctt cta ttg ccc gaa ggg ttt cga gaa 700Asn Phe Leu Arg Asn
Gly Glu Leu Leu Leu Pro Glu Gly Phe Arg Glu 95
100 105aat caa ctt ctt gca caa gaa gca gaa ttc ttt
cag ctc aag gga ctg 748Asn Gln Leu Leu Ala Gln Glu Ala Glu Phe Phe
Gln Leu Lys Gly Leu 110 115
120gca gag gaa gtg aaa tcc agg tgg gag aaa gaa cag cta aca ccc aga
796Ala Glu Glu Val Lys Ser Arg Trp Glu Lys Glu Gln Leu Thr Pro Arg
125 130 135gag act act ttc ttg gaa ata
aca gat aac cac gat cgt tca caa gga 844Glu Thr Thr Phe Leu Glu Ile
Thr Asp Asn His Asp Arg Ser Gln Gly 140 145
150tta aga atc ttc tgt aat gct cct gat ttc ata tca aaa ata aag tct
892Leu Arg Ile Phe Cys Asn Ala Pro Asp Phe Ile Ser Lys Ile Lys Ser155
160 165 170cgc att gtt ctg
gtg tcc aaa agc agg ctg gat gga ttt cca gag gag 940Arg Ile Val Leu
Val Ser Lys Ser Arg Leu Asp Gly Phe Pro Glu Glu 175
180 185ttt tca ata tcg tca aat atc atc caa ttt
aaa tac ttc ata aag tct 988Phe Ser Ile Ser Ser Asn Ile Ile Gln Phe
Lys Tyr Phe Ile Lys Ser 190 195
200gaa aat ggc act cga ctt gta cta aag gaa gac aac acc ttt gtc tgt
1036Glu Asn Gly Thr Arg Leu Val Leu Lys Glu Asp Asn Thr Phe Val Cys
205 210 215acc ttg gaa act ctt aag ttt
gag gct atc atg atg gct tta aag tgt 1084Thr Leu Glu Thr Leu Lys Phe
Glu Ala Ile Met Met Ala Leu Lys Cys 220 225
230ggc ttt aga ctg ctg acc agc ctg gat tgt tcc aaa ggg tca att gtt
1132Gly Phe Arg Leu Leu Thr Ser Leu Asp Cys Ser Lys Gly Ser Ile Val235
240 245 250cac agc gat gca
ctt cat ttt atc a agtaattacc tgtgtcacga 1177His Ser Asp Ala
Leu His Phe Ile 255acaaaggcaa caagcatgca gccagcaagc
ttcggaaaac cacagcatca aagacatccc 1237aaataacatg cccagctagc tctgtactac
agagccctgc tactaatcaa ttactgtgag 1297ctaacggtat gtaaattcta tcgctaaaga
tgtccttcct ctggggtgtt cctactgatc 1357agactcttcc acctaaaatg aaaacagtaa
ccttctatat actgtaaata aagactgaaa 1417gcttttgcta tttatttgtc cttaagctgt
ctttcaattc agattgtctt gggtatttgc 1477acaaaaagaa gcatgtacat tatctatcgt
tcatttaagt aaatggtaat aaaatatttt 1537aaggggctat taatatttaa aatccttttc
tactatggca aaaatctaca gagaaactga 1597actggcaaaa ttaactacct ggagcaaaac
agatgtgcag atctaactaa aacagagcta 1657tagtgaaaca aaatgagatt gtaagaagac
attaaagcta ttgatttgat ttttccatag 1717caagcaccaa aagcttatat tcacagttcc
tgtgtttcat attagactta tagctgaatt 1777ggtattttgc tgaaaattcc tagaaaactg
cttgatgaca ataaaaagta aataaaagca 1837ctgctacctt caaaaaaaaa aaaaa
186212258PRTH. sapiens 12Met Glu Arg Lys
Ile Asn Arg Arg Glu Lys Glu Lys Glu Tyr Glu Gly1 5
10 15Lys His Asn Ser Leu Glu Asp Thr Asp Gln Gly
Lys Asn Cys Lys Ser 20 25
30Thr Leu Met Thr Leu Asn Val Gly Gly Tyr Leu Tyr Ile Thr Gln Lys
35 40 45Gln Thr Leu Thr Lys Tyr Pro Asp
Thr Phe Leu Glu Gly Ile Val Asn 50 55
60Gly Lys Ile Leu Cys Pro Phe Asp Ala Asp Gly His Tyr Phe Ile Asp65
70 75 80Arg Asp Gly Leu Leu
Phe Arg His Val Leu Asn Phe Leu Arg Asn Gly 85
90 95Glu Leu Leu Leu Pro Glu Gly Phe Arg Glu Asn
Gln Leu Leu Ala Gln 100 105
110Glu Ala Glu Phe Phe Gln Leu Lys Gly Leu Ala Glu Glu Val Lys Ser
115 120 125Arg Trp Glu Lys Glu Gln Leu
Thr Pro Arg Glu Thr Thr Phe Leu Glu 130 135
140Ile Thr Asp Asn His Asp Arg Ser Gln Gly Leu Arg Ile Phe Cys
Asn145 150 155 160Ala Pro
Asp Phe Ile Ser Lys Ile Lys Ser Arg Ile Val Leu Val Ser
165 170 175Lys Ser Arg Leu Asp Gly Phe
Pro Glu Glu Phe Ser Ile Ser Ser Asn 180 185
190Ile Ile Gln Phe Lys Tyr Phe Ile Lys Ser Glu Asn Gly Thr
Arg Leu 195 200 205Val Leu Lys Glu
Asp Asn Thr Phe Val Cys Thr Leu Glu Thr Leu Lys 210
215 220Phe Glu Ala Ile Met Met Ala Leu Lys Cys Gly Phe
Arg Leu Leu Thr225 230 235
240Ser Leu Asp Cys Ser Lys Gly Ser Ile Val His Ser Asp Ala Leu His
245 250 255Phe Ile131877DNAH.
sapiensCDS(322)...(1090)K+Hnov27 13caccaccgcc cccagccgcc ctcgctgggg
aacacttaca tcctccccaa agacagccag 60gtcgggcccg acgtgaaatc cgaggctgcg
cccaagcgcg ccctgtacga gtctgtgttc 120gggtcggggg aaatctgcgg ccccacttcc
cccaaaagac tttgtatccg cccctcggag 180cctgtggatg cggtggtggt ggtttccgtg
aaacacgacc ccctgcctct tcttccagaa 240gccaatgggc acagaagcac caattctccc
acaatagttt cacctgctat tgtttccccc 300acccaggaca gtcggcccaa t atg tca
aga cct ctg atc act aga tcc cct 351Met Ser Arg Pro Leu Ile Thr Arg
Ser Pro1 5 10gca tct cca ctg awc aac caa
ggc atc cct act cca gca caa ctc aca 399Ala Ser Pro Leu Xaa Asn Gln
Gly Ile Pro Thr Pro Ala Gln Leu Thr 15 20
25aaa tcc aat gcg cct gtc cac att gat gtg ggc ggc cac
atg tac acc 447Lys Ser Asn Ala Pro Val His Ile Asp Val Gly Gly His
Met Tyr Thr 30 35 40agc agc
ctg gcc acc ctc acc aaa tac cct gaa tcc aga atc gga aga 495Ser Ser
Leu Ala Thr Leu Thr Lys Tyr Pro Glu Ser Arg Ile Gly Arg 45
50 55ctt ttt gat ggt aca gag ccc att gtt ttg
gac agt ctc aaa cag cac 543Leu Phe Asp Gly Thr Glu Pro Ile Val Leu
Asp Ser Leu Lys Gln His 60 65 70tat
ttc att gac aga gat gga cag atg ttc aga tat atc ttg aat ttt 591Tyr
Phe Ile Asp Arg Asp Gly Gln Met Phe Arg Tyr Ile Leu Asn Phe75
80 85 90cta cga aca tcc aaa ctc
ctc att cct gat gat ttc aag gac tac act 639Leu Arg Thr Ser Lys Leu
Leu Ile Pro Asp Asp Phe Lys Asp Tyr Thr 95
100 105ttg tta tat gaa gag gca aaa tat ttt cag ctt cag
ccc atg ttg ttg 687Leu Leu Tyr Glu Glu Ala Lys Tyr Phe Gln Leu Gln
Pro Met Leu Leu 110 115 120gag
atg gaa aga tgg aag cag gac aga gaa act ggt cga ttt tca agg 735Glu
Met Glu Arg Trp Lys Gln Asp Arg Glu Thr Gly Arg Phe Ser Arg 125
130 135ccc tgt gag tgc ctc gtc gtg cgt gtg
gcc cca gac ctc gga gaa agg 783Pro Cys Glu Cys Leu Val Val Arg Val
Ala Pro Asp Leu Gly Glu Arg 140 145
150atc acg cta agc ggt gac aaa tcc ttg ata gaa gaa gta ttt cca gag
831Ile Thr Leu Ser Gly Asp Lys Ser Leu Ile Glu Glu Val Phe Pro Glu155
160 165 170atc ggc gac gtg
atg tgt aac tct gtc aat gca ggc tgg aat cac gac 879Ile Gly Asp Val
Met Cys Asn Ser Val Asn Ala Gly Trp Asn His Asp 175
180 185tcg acg cac gtc atc agg ttt cca cta aat
ggc tac tgt cac ctc aac 927Ser Thr His Val Ile Arg Phe Pro Leu Asn
Gly Tyr Cys His Leu Asn 190 195
200tca gtc cag gtc ctc gag agg ttg cag caa aga gga ttt gaa atc gtg
975Ser Val Gln Val Leu Glu Arg Leu Gln Gln Arg Gly Phe Glu Ile Val
205 210 215ggc tcc tgt ggg gga gga gta
gac tcg tcc cag ttc agc gaa tac gtc 1023Gly Ser Cys Gly Gly Gly Val
Asp Ser Ser Gln Phe Ser Glu Tyr Val 220 225
230ctt cgg cgg gaa ctg agg cgg acg ccc cgt gta ccc tcc gtc atc cgg
1071Leu Arg Arg Glu Leu Arg Arg Thr Pro Arg Val Pro Ser Val Ile Arg235
240 245 250ata aag caa gag
cct ctg g actaaatgga catatttctt atgcaaaaag 1120Ile Lys Gln Glu
Pro Leu 255gaaaacacac acaaccaata actcaaacaa aaaagggaca
tttatgtgca gttgggacag 1180caaaccaagt cctggacgta aaattgaata aaagacacat
ttatatccaa tagagaccac 1240acctgtattc atatgggaac aattggaata gtgatatcct
caaggtgtaa aaaatatata 1300aatatatata tatatgtcaa aaggtaggaa atgcaaaaaa
gaaaaaaaaa aaaggtgaca 1360gccgcagttg gtgctgtgat ggccgtgaag tgtcctgggc
ctcccgaggc ctctgacaaa 1420taaacaagcc atgagtggtg aggacacagt ctccttacag
tttccattgc caacaacagc 1480catccatatt tcttttttcc tttgtctttc tttttccttt
ttttttaaaa aaacaaaaca 1540aacaaaacac cttgaatcaa gtttgtttgt atatggaggt
tccacgtctt tctttaggca 1600gggaccaggc aggacttcag aaaaaccctc atgagcacat
tgcaaagatg ttagacatga 1660aattttaaat gtagtttgta cagaagtcac acttttttgt
ccacctcaca gatgtgaact 1720ttactttgtt ttaaaactga tcagttttgc caaggggcca
gaattattcc ttgttagaat 1780tgctccagtt caagtctgct gctttcctac aatttttcaa
attttataat gtattaaata 1840caataaactc tgtttaaaaa ataaaaaaaa aaaaaaa
187714256PRTH. sapiensVARIANT(1)...(256)Xaa = Any
Amino Acid 14Met Ser Arg Pro Leu Ile Thr Arg Ser Pro Ala Ser Pro Leu Xaa
Asn1 5 10 15Gln Gly Ile
Pro Thr Pro Ala Gln Leu Thr Lys Ser Asn Ala Pro Val 20
25 30His Ile Asp Val Gly Gly His Met Tyr Thr
Ser Ser Leu Ala Thr Leu 35 40
45Thr Lys Tyr Pro Glu Ser Arg Ile Gly Arg Leu Phe Asp Gly Thr Glu 50
55 60Pro Ile Val Leu Asp Ser Leu Lys Gln
His Tyr Phe Ile Asp Arg Asp65 70 75
80Gly Gln Met Phe Arg Tyr Ile Leu Asn Phe Leu Arg Thr Ser
Lys Leu 85 90 95Leu Ile
Pro Asp Asp Phe Lys Asp Tyr Thr Leu Leu Tyr Glu Glu Ala 100
105 110Lys Tyr Phe Gln Leu Gln Pro Met Leu
Leu Glu Met Glu Arg Trp Lys 115 120
125Gln Asp Arg Glu Thr Gly Arg Phe Ser Arg Pro Cys Glu Cys Leu Val
130 135 140Val Arg Val Ala Pro Asp Leu
Gly Glu Arg Ile Thr Leu Ser Gly Asp145 150
155 160Lys Ser Leu Ile Glu Glu Val Phe Pro Glu Ile Gly
Asp Val Met Cys 165 170
175Asn Ser Val Asn Ala Gly Trp Asn His Asp Ser Thr His Val Ile Arg
180 185 190Phe Pro Leu Asn Gly Tyr
Cys His Leu Asn Ser Val Gln Val Leu Glu 195 200
205Arg Leu Gln Gln Arg Gly Phe Glu Ile Val Gly Ser Cys Gly
Gly Gly 210 215 220Val Asp Ser Ser Gln
Phe Ser Glu Tyr Val Leu Arg Arg Glu Leu Arg225 230
235 240Arg Thr Pro Arg Val Pro Ser Val Ile Arg
Ile Lys Gln Glu Pro Leu 245 250
25515923DNAH. sapiensCDS(165)...(756)K+Hnov2 15gcgtggtggc aggtgcctgt
agccccagct acttgggagg ctgaggcagg agaatagctt 60gaacccgggc ggcgaaggtt
gagtgagccg agattgcacc actgcactcc agcctgggcg 120acagagcgag actccatctc
aaaaaaaaga gtagttatgg ccac atg gcc cca cta 176Met Ala Pro Leu1tcg cca
ggc gga aag gcc ttc tgc atg gtc tat gca gcc ctg ggg ctg 224Ser Pro
Gly Gly Lys Ala Phe Cys Met Val Tyr Ala Ala Leu Gly Leu5
10 15 20cca gcc tcc tta gct ctc gtg
gcc acc ctg cgc cat tgc ctg ctg cct 272Pro Ala Ser Leu Ala Leu Val
Ala Thr Leu Arg His Cys Leu Leu Pro 25 30
35gtg ctc agc cgc cca cgt gcc tgg gta gcg gtc cac tgg
cag ctg tca 320Val Leu Ser Arg Pro Arg Ala Trp Val Ala Val His Trp
Gln Leu Ser 40 45 50ccg gcc
agg gct gcg ctg ctg cag gca gtt gca ctg gga ctg ctg gtg 368Pro Ala
Arg Ala Ala Leu Leu Gln Ala Val Ala Leu Gly Leu Leu Val 55
60 65gcc agc agc ttt gtg ctg ctg cca gcg ctg
gtg ctg tgg ggc ctt cag 416Ala Ser Ser Phe Val Leu Leu Pro Ala Leu
Val Leu Trp Gly Leu Gln 70 75 80ggc
gac tgc agc ctg ctg ggg gcc gtc tac ttc tgc ttc agc tcg ctc 464Gly
Asp Cys Ser Leu Leu Gly Ala Val Tyr Phe Cys Phe Ser Ser Leu85
90 95 100agc acc att ggc ctg gag
gac ttg ctg ccc ggc cgc ggc cgc agc ctg 512Ser Thr Ile Gly Leu Glu
Asp Leu Leu Pro Gly Arg Gly Arg Ser Leu 105
110 115cac ccc gtg att tac cac ctg ggc cag ctc gca ctt
ctt ggt tac ttg 560His Pro Val Ile Tyr His Leu Gly Gln Leu Ala Leu
Leu Gly Tyr Leu 120 125 130ctt
cta gga ctc ttg gcc atg ctg ctg gca gtg gag acc ttc tct gag 608Leu
Leu Gly Leu Leu Ala Met Leu Leu Ala Val Glu Thr Phe Ser Glu 135
140 145ctg ccg cag gtc cgt gcc atg ggg aag
ttc ttc aga ccc agt ggt cct 656Leu Pro Gln Val Arg Ala Met Gly Lys
Phe Phe Arg Pro Ser Gly Pro 150 155
160gtg act gct gag gac caa ggt ggc atc cta ggg cag gat gaa ctg gct
704Val Thr Ala Glu Asp Gln Gly Gly Ile Leu Gly Gln Asp Glu Leu Ala165
170 175 180ctg agc acc ctg
ccg ccc gcg gcc cca gct tca gga caa gcc cct gct 752Leu Ser Thr Leu
Pro Pro Ala Ala Pro Ala Ser Gly Gln Ala Pro Ala 185
190 195tgc t gaagcgtcag gtgaccgagt tcagctccgt
aaggtggcgg cacctgagga 806Cysggaagcagcc aggagtggct ggggaagaat
ctggagatgg agccgcggtg agggtgggcg 866ggaggcctca ggggatactg ttaatcataa
aaaaaaaaaa aaaaaaaaaa aaaaaaa 92316197PRTH. sapiens 16Met Ala Pro
Leu Ser Pro Gly Gly Lys Ala Phe Cys Met Val Tyr Ala1 5
10 15Ala Leu Gly Leu Pro Ala Ser Leu Ala Leu
Val Ala Thr Leu Arg His 20 25
30Cys Leu Leu Pro Val Leu Ser Arg Pro Arg Ala Trp Val Ala Val His
35 40 45Trp Gln Leu Ser Pro Ala Arg Ala
Ala Leu Leu Gln Ala Val Ala Leu 50 55
60Gly Leu Leu Val Ala Ser Ser Phe Val Leu Leu Pro Ala Leu Val Leu65
70 75 80Trp Gly Leu Gln Gly
Asp Cys Ser Leu Leu Gly Ala Val Tyr Phe Cys 85
90 95Phe Ser Ser Leu Ser Thr Ile Gly Leu Glu Asp
Leu Leu Pro Gly Arg 100 105
110Gly Arg Ser Leu His Pro Val Ile Tyr His Leu Gly Gln Leu Ala Leu
115 120 125Leu Gly Tyr Leu Leu Leu Gly
Leu Leu Ala Met Leu Leu Ala Val Glu 130 135
140Thr Phe Ser Glu Leu Pro Gln Val Arg Ala Met Gly Lys Phe Phe
Arg145 150 155 160Pro Ser
Gly Pro Val Thr Ala Glu Asp Gln Gly Gly Ile Leu Gly Gln
165 170 175Asp Glu Leu Ala Leu Ser Thr
Leu Pro Pro Ala Ala Pro Ala Ser Gly 180 185
190Gln Ala Pro Ala Cys 195173102DNAH.
sapiensCDS(274)...(1705)K+Hnov11 17gcacgcgcaa agcgcccacc gagacccctg
gggtggagct tgtgttaata gaaacatacc 60cacccccagc ctttcctggg aggggatcag
acccctcaaa ctcttgcccc agcccagccc 120ttcagcaccc aagacccacc aggaggcctg
ggcccgccag taatgggtag ggagaggggg 180ccccgccagg gcgcacggcg ctctcgccga
cgctgttccc tccgcttcca ggtgtagcgc 240ccccgcgcgg cgcgggcggc cggcgcctcc
agc atg acc ggc cag agc ctg tgg 294Met Thr Gly Gln Ser Leu Trp1
5gac gtg tcg gag gct aac gtc gag gac ggg gag atc cgc atc aat gtg
342Asp Val Ser Glu Ala Asn Val Glu Asp Gly Glu Ile Arg Ile Asn Val
10 15 20ggc ggc ttc aag agg agg ctg
cgc tcg cac acg ctg ctg cgc ttc ccc 390Gly Gly Phe Lys Arg Arg Leu
Arg Ser His Thr Leu Leu Arg Phe Pro 25 30
35gag acg cgc ctg ggc cgc ttg ctg ctc tgc cac tcg cgc gag gcc att
438Glu Thr Arg Leu Gly Arg Leu Leu Leu Cys His Ser Arg Glu Ala Ile40
45 50 55ctg gag ctc tgc
gat gac tac gac gac gtc cag cgg gag ttc tac ttc 486Leu Glu Leu Cys
Asp Asp Tyr Asp Asp Val Gln Arg Glu Phe Tyr Phe 60
65 70gac cgc aac cct gag ctc ttc ccc tac gtg
ctg cat ttc tat cac acc 534Asp Arg Asn Pro Glu Leu Phe Pro Tyr Val
Leu His Phe Tyr His Thr 75 80
85ggc aag ctt cac gtc atg gct gag cta tgt gtc ttc tcc ttc agc cag
582Gly Lys Leu His Val Met Ala Glu Leu Cys Val Phe Ser Phe Ser Gln
90 95 100gag atc gag tac tgg ggc atc aac
gag ttc ttc att gac tcc tgc tgc 630Glu Ile Glu Tyr Trp Gly Ile Asn
Glu Phe Phe Ile Asp Ser Cys Cys 105 110
115agc tac agc tac cat ggc cgc aaa gta gag ccc gag cag gag aag tgg
678Ser Tyr Ser Tyr His Gly Arg Lys Val Glu Pro Glu Gln Glu Lys Trp120
125 130 135gac gag cag agt
gac cag gag agc acc acg tct tcc ttc gat gag atc 726Asp Glu Gln Ser
Asp Gln Glu Ser Thr Thr Ser Ser Phe Asp Glu Ile 140
145 150ctt gcc ttc tac aac gac gcc tcc aag ttc
gat ggg cag ccc ctc ggc 774Leu Ala Phe Tyr Asn Asp Ala Ser Lys Phe
Asp Gly Gln Pro Leu Gly 155 160
165aac ttc cgc agg cag ctg tgg ctg gcg ctg gac aac ccc ggc tac tca
822Asn Phe Arg Arg Gln Leu Trp Leu Ala Leu Asp Asn Pro Gly Tyr Ser
170 175 180gtg ctg agc agg gtc ttc agc
atc ctg tcc atc ctg gtg gtg atg ggg 870Val Leu Ser Arg Val Phe Ser
Ile Leu Ser Ile Leu Val Val Met Gly 185 190
195tcc atc atc acc atg tgc ctc aat agc ctg ccc gat ttc caa atc cct
918Ser Ile Ile Thr Met Cys Leu Asn Ser Leu Pro Asp Phe Gln Ile Pro200
205 210 215gac agc cag ggc
aac cct ggc gag gac cct agg ttc gaa atc gtg gag 966Asp Ser Gln Gly
Asn Pro Gly Glu Asp Pro Arg Phe Glu Ile Val Glu 220
225 230cac ttt ggc att gcc tgg ttc aca ttt gag
ctg gtg gcc agg ttt gct 1014His Phe Gly Ile Ala Trp Phe Thr Phe Glu
Leu Val Ala Arg Phe Ala 235 240
245gtg gcc cct gac ttc ctc aag ttc ttc aag aat gcc cta aac ctt att
1062Val Ala Pro Asp Phe Leu Lys Phe Phe Lys Asn Ala Leu Asn Leu Ile
250 255 260gac ctc atg tcc atc gtc ccc
ttt tac atc act ctg gtg gtg aac ctg 1110Asp Leu Met Ser Ile Val Pro
Phe Tyr Ile Thr Leu Val Val Asn Leu 265 270
275gtg gtg gag agc aca cct act tta gcc aac ttg ggc agg gtg gcc cag
1158Val Val Glu Ser Thr Pro Thr Leu Ala Asn Leu Gly Arg Val Ala Gln280
285 290 295gtc ctg agg ctg
atg cgg atc ttc cgc atc tta aag ctg gcc agg cac 1206Val Leu Arg Leu
Met Arg Ile Phe Arg Ile Leu Lys Leu Ala Arg His 300
305 310tcc act ggc ctc cgc tcc ctg ggg gcc act
ttg aaa tac agc tac aaa 1254Ser Thr Gly Leu Arg Ser Leu Gly Ala Thr
Leu Lys Tyr Ser Tyr Lys 315 320
325gaa gta ggg ctg ctc ttg ctc tac ctc tcc gtg ggg att tcc atc ttc
1302Glu Val Gly Leu Leu Leu Leu Tyr Leu Ser Val Gly Ile Ser Ile Phe
330 335 340tcc gtg gtg gcc tac acc att
gaa aag gag gag aac gag ggc ctg gcc 1350Ser Val Val Ala Tyr Thr Ile
Glu Lys Glu Glu Asn Glu Gly Leu Ala 345 350
355acc atc cct gcc tgc tgg tgg tgg gct acc gtc agt atg acc aca gtg
1398Thr Ile Pro Ala Cys Trp Trp Trp Ala Thr Val Ser Met Thr Thr Val360
365 370 375ggg tac ggg gat
gtg gtc cca ggg acc acg gca gga aag ctg act gcc 1446Gly Tyr Gly Asp
Val Val Pro Gly Thr Thr Ala Gly Lys Leu Thr Ala 380
385 390tct gcc tgc atc ttg gca ggc atc ctc gtg
gtg gtc ctg ccc atc acc 1494Ser Ala Cys Ile Leu Ala Gly Ile Leu Val
Val Val Leu Pro Ile Thr 395 400
405ttg atc ttc aat aag ttc tcc cac ttt tac cgg cgc caa aag caa ctt
1542Leu Ile Phe Asn Lys Phe Ser His Phe Tyr Arg Arg Gln Lys Gln Leu
410 415 420gag agt gcc atg cgc agc tgt
gac ttt gga gat gga atg aag gag gtc 1590Glu Ser Ala Met Arg Ser Cys
Asp Phe Gly Asp Gly Met Lys Glu Val 425 430
435cct tcg gtc aat tta agg gac tat tat gcc cat aaa gtt aaa tcc ctt
1638Pro Ser Val Asn Leu Arg Asp Tyr Tyr Ala His Lys Val Lys Ser Leu440
445 450 455atg gca agc ctg
acg aac atg agc agg agc tca cca agt gaa ctc agt 1686Met Ala Ser Leu
Thr Asn Met Ser Arg Ser Ser Pro Ser Glu Leu Ser 460
465 470tta aat gat tcc cta cgt t agccgggagg
acttgtcacc ctccacccca 1735Leu Asn Asp Ser Leu Arg
475cattgctgag ctgcctcttg tgcctctggc acagcccagg caccttatgg ttatggtgta
1795aggagtatgc ccagcccctg aggggagaga tgcatgggat atgcacccag gtttctttta
1855cagtttttag aatcgttttt agagggtggt gtgtctgaca ccatgccttt gcacctttcc
1915atgaaatgac actcactggt ctttgcatcg tgggcataaa atgttcacct tttttccaga
1975tgagtacacc cagaatgcta atttttctgt ccatcgtgta cgctattcta gtgcttgtgg
2035cccagtactg tctatgagtt gtcgtgctcc tgtttctgag gttgtcgtgt gagttctgta
2095caaaaagccc ccacaagtcg tccagtagaa atgcatctat gaggtcagca aggatatgat
2155gagattttgc tcacagtcat gtgaaaacaa aatctcagct ctttatccat tgctttcact
2215tagttttagt accaaaacaa agagaatgca aagttaagca gacttgacca atgcaagtct
2275ctaagttgtt tttataaatg atctgtagtt ccgtggcttg catgggtgca ccaatcatct
2335ttagaacgat gtacactgat gttcatctca taaatgtcac tctttagaga atgttactta
2395gttaaacatg cagtgaagat cgaatttttt tcccaagaac agatgtgtta gggagagggg
2455cttcagctaa atagtccaaa ccctagggtg cttaaagcca agttagtgca ggctgagccc
2515cttggttcac agtcaagcct ccttgtttcc tagggtgact gtagagaaat gtatttccgg
2575atgaggtttc tgatctaggc catttgacca aactttgctg tgtctaagat attagcatgt
2635ttttgaaata tttatttttt aagatgttta ggagtaaggt cgtgttgtct tcctcaacta
2695aaaagaagtt tactgttgta tcgtctccct gaggtgaacg ttgttgggtt gctagcaagg
2755cagtagctta atacttttgt tgcctactct gaaagctcat caatgagagc ccttttattt
2815ccaagcagaa tttagtcaga taattttgct tctaggatat agtatgttgt atatgatgct
2875gtgattgccc tggagttcct gcccatgact ggaaacctgg tggtatggaa gcatgtactc
2935aaaatataga cgtgcacgat ggtggtgtgg cttacccagg atggaaacac tgcagttctt
2995acttgcattc ccactgcctt tcatgggggg tgactgggta gaggccagga gaaaggaaag
3055agttgtaaaa taaaaaactg ctagttcata aaaaaaaaaa aaaaaaa
310218477PRTH. sapiens 18Met Thr Gly Gln Ser Leu Trp Asp Val Ser Glu Ala
Asn Val Glu Asp1 5 10
15Gly Glu Ile Arg Ile Asn Val Gly Gly Phe Lys Arg Arg Leu Arg Ser
20 25 30His Thr Leu Leu Arg Phe Pro
Glu Thr Arg Leu Gly Arg Leu Leu Leu 35 40
45Cys His Ser Arg Glu Ala Ile Leu Glu Leu Cys Asp Asp Tyr Asp
Asp 50 55 60Val Gln Arg Glu Phe Tyr
Phe Asp Arg Asn Pro Glu Leu Phe Pro Tyr65 70
75 80Val Leu His Phe Tyr His Thr Gly Lys Leu His
Val Met Ala Glu Leu 85 90
95Cys Val Phe Ser Phe Ser Gln Glu Ile Glu Tyr Trp Gly Ile Asn Glu
100 105 110Phe Phe Ile Asp Ser Cys
Cys Ser Tyr Ser Tyr His Gly Arg Lys Val 115 120
125Glu Pro Glu Gln Glu Lys Trp Asp Glu Gln Ser Asp Gln Glu
Ser Thr 130 135 140Thr Ser Ser Phe Asp
Glu Ile Leu Ala Phe Tyr Asn Asp Ala Ser Lys145 150
155 160Phe Asp Gly Gln Pro Leu Gly Asn Phe Arg
Arg Gln Leu Trp Leu Ala 165 170
175Leu Asp Asn Pro Gly Tyr Ser Val Leu Ser Arg Val Phe Ser Ile Leu
180 185 190Ser Ile Leu Val Val
Met Gly Ser Ile Ile Thr Met Cys Leu Asn Ser 195
200 205Leu Pro Asp Phe Gln Ile Pro Asp Ser Gln Gly Asn
Pro Gly Glu Asp 210 215 220Pro Arg Phe
Glu Ile Val Glu His Phe Gly Ile Ala Trp Phe Thr Phe225
230 235 240Glu Leu Val Ala Arg Phe Ala
Val Ala Pro Asp Phe Leu Lys Phe Phe 245
250 255Lys Asn Ala Leu Asn Leu Ile Asp Leu Met Ser Ile
Val Pro Phe Tyr 260 265 270Ile
Thr Leu Val Val Asn Leu Val Val Glu Ser Thr Pro Thr Leu Ala 275
280 285Asn Leu Gly Arg Val Ala Gln Val Leu
Arg Leu Met Arg Ile Phe Arg 290 295
300Ile Leu Lys Leu Ala Arg His Ser Thr Gly Leu Arg Ser Leu Gly Ala305
310 315 320Thr Leu Lys Tyr
Ser Tyr Lys Glu Val Gly Leu Leu Leu Leu Tyr Leu 325
330 335Ser Val Gly Ile Ser Ile Phe Ser Val Val
Ala Tyr Thr Ile Glu Lys 340 345
350Glu Glu Asn Glu Gly Leu Ala Thr Ile Pro Ala Cys Trp Trp Trp Ala
355 360 365Thr Val Ser Met Thr Thr Val
Gly Tyr Gly Asp Val Val Pro Gly Thr 370 375
380Thr Ala Gly Lys Leu Thr Ala Ser Ala Cys Ile Leu Ala Gly Ile
Leu385 390 395 400Val Val
Val Leu Pro Ile Thr Leu Ile Phe Asn Lys Phe Ser His Phe
405 410 415Tyr Arg Arg Gln Lys Gln Leu
Glu Ser Ala Met Arg Ser Cys Asp Phe 420 425
430Gly Asp Gly Met Lys Glu Val Pro Ser Val Asn Leu Arg Asp
Tyr Tyr 435 440 445Ala His Lys Val
Lys Ser Leu Met Ala Ser Leu Thr Asn Met Ser Arg 450
455 460Ser Ser Pro Ser Glu Leu Ser Leu Asn Asp Ser Leu
Arg465 470 475193857DNAH.
sapiensCDS(249)...(3495)K+Hnov14 19gggctggtag cagggatttg tgggcggcga
gggcgcgagg ggccgcgcgc catgctccgg 60gccccgacgg cgcggacgcc ccctcgcgcg
ccagctccgg cgcgaccccg gatcccggtc 120tgcgcattgc cccccgacgg ctgcgctagg
agcgcggggc ccggcggggg cggccgagct 180gggcgccctc ccccggcgcg gagtccccgc
accccggagg atggggcggg cagccgcggg 240cgcctaag atg ccg gcc atg cgg ggc
ctc ctg gcg ccg cag aac acc ttc 290Met Pro Ala Met Arg Gly Leu Leu
Ala Pro Gln Asn Thr Phe1 5 10ctg gac acc
atc gct acg cgc ttc gac ggc acg cac agt aac ttc gtg 338Leu Asp Thr
Ile Ala Thr Arg Phe Asp Gly Thr His Ser Asn Phe Val15 20
25 30ctg ggc aac gcc agt ggc ggg gct
ctt ccc gtg gtc tac tgc tct gat 386Leu Gly Asn Ala Ser Gly Gly Ala
Leu Pro Val Val Tyr Cys Ser Asp 35 40
45ggc ttc tgt gac ctc acg ggc ttc tcc cgg gct gag gtc atg
cag cgg 434Gly Phe Cys Asp Leu Thr Gly Phe Ser Arg Ala Glu Val Met
Gln Arg 50 55 60ggc tgt gcc
tgc tcc ttc ctt tat ggg cca gac acc agt gag ctc gtc 482Gly Cys Ala
Cys Ser Phe Leu Tyr Gly Pro Asp Thr Ser Glu Leu Val 65
70 75cgc caa cag atc cgc aag gcc ctg gac gag cac
aag gag ttc aag gct 530Arg Gln Gln Ile Arg Lys Ala Leu Asp Glu His
Lys Glu Phe Lys Ala 80 85 90gag ctg
atc ctg tac cgg aag agc ggg ctc ccg ttc tgg tgt ctc ctg 578Glu Leu
Ile Leu Tyr Arg Lys Ser Gly Leu Pro Phe Trp Cys Leu Leu95
100 105 110gat gtg ata ccc ata aag aat
gag aaa ggg gag gtg gct ctc ttc cta 626Asp Val Ile Pro Ile Lys Asn
Glu Lys Gly Glu Val Ala Leu Phe Leu 115
120 125gtc tct cac aag gac atc agc gaa acc aag aac cga
ggg ggc ccc gac 674Val Ser His Lys Asp Ile Ser Glu Thr Lys Asn Arg
Gly Gly Pro Asp 130 135 140aga
tgg aaa gag aca ggt ggt ggc cgg cgc cga tat ggc cgg gca cga 722Arg
Trp Lys Glu Thr Gly Gly Gly Arg Arg Arg Tyr Gly Arg Ala Arg 145
150 155tcc aaa ggc ttc aat gcc aac cgg cgg
cgg agc cgg gcc gtg ctc tac 770Ser Lys Gly Phe Asn Ala Asn Arg Arg
Arg Ser Arg Ala Val Leu Tyr 160 165
170cac ctg tcc ggg cac ctg cag aag cag ccc aag ggc aag cac aag ctc
818His Leu Ser Gly His Leu Gln Lys Gln Pro Lys Gly Lys His Lys Leu175
180 185 190aat aag ggg gtg
ttt ggg gag aaa cca aac ttg cct gag tac aaa gta 866Asn Lys Gly Val
Phe Gly Glu Lys Pro Asn Leu Pro Glu Tyr Lys Val 195
200 205gcc gcc atc cgg aag tcg ccc ttc atc ctg
ttg cac tgt ggg gca ctg 914Ala Ala Ile Arg Lys Ser Pro Phe Ile Leu
Leu His Cys Gly Ala Leu 210 215
220aga gcc acc tgg gat ggc ttc atc ctg ctc gcc aca ctc tat gtg gct
962Arg Ala Thr Trp Asp Gly Phe Ile Leu Leu Ala Thr Leu Tyr Val Ala
225 230 235gtc act gtg ccc tac agc gtg
tgt gtg agc aca gca cgg gag ccc agt 1010Val Thr Val Pro Tyr Ser Val
Cys Val Ser Thr Ala Arg Glu Pro Ser 240 245
250gcc gcc cgc ggc ccg ccc agc gtc tgt gac ctg gcc gtg gag gtc ctc
1058Ala Ala Arg Gly Pro Pro Ser Val Cys Asp Leu Ala Val Glu Val Leu255
260 265 270ttc atc ctt gac
att gtg ctg aat ttc cgt acc aca ttc gtg tcc aag 1106Phe Ile Leu Asp
Ile Val Leu Asn Phe Arg Thr Thr Phe Val Ser Lys 275
280 285tcg ggc cag gtg gtg ttt gcc cca aag tcc
att tgc ctc cac tac gtc 1154Ser Gly Gln Val Val Phe Ala Pro Lys Ser
Ile Cys Leu His Tyr Val 290 295
300acc acc tgg ttc ctg ctg gat gtc atc gca gcg ctg ccc ttt gac ctg
1202Thr Thr Trp Phe Leu Leu Asp Val Ile Ala Ala Leu Pro Phe Asp Leu
305 310 315cta cat gcc ttc aag gtc aac
gtg tac ttc ggg gcc cat ctg ctg aag 1250Leu His Ala Phe Lys Val Asn
Val Tyr Phe Gly Ala His Leu Leu Lys 320 325
330acg gtg cgc ctg ctg cgc ctg ctg cgc ctg ctt ccg cgg ctg gac cgg
1298Thr Val Arg Leu Leu Arg Leu Leu Arg Leu Leu Pro Arg Leu Asp Arg335
340 345 350tac tcg cag tac
agc gcc gtg gtg ctg aca ctg ctc atg gcc gtg ttc 1346Tyr Ser Gln Tyr
Ser Ala Val Val Leu Thr Leu Leu Met Ala Val Phe 355
360 365gcc ctg ctc gcg cac tgg gtc gcc tgc gtc
tgg ttt tac att ggc cag 1394Ala Leu Leu Ala His Trp Val Ala Cys Val
Trp Phe Tyr Ile Gly Gln 370 375
380cgg gag atc gag agc agc gaa tcc gag ctg cct gag att ggc tgg ctg
1442Arg Glu Ile Glu Ser Ser Glu Ser Glu Leu Pro Glu Ile Gly Trp Leu
385 390 395cag gag ctg gcc cgc cga ctg
gag act ccc tac tac ctg gtg ggc cgg 1490Gln Glu Leu Ala Arg Arg Leu
Glu Thr Pro Tyr Tyr Leu Val Gly Arg 400 405
410agg cca gct gga ggg aac agc tcc ggc cag agt gac aac tgc agc agc
1538Arg Pro Ala Gly Gly Asn Ser Ser Gly Gln Ser Asp Asn Cys Ser Ser415
420 425 430agc agc gag gcc
aac ggg acg ggg ctg gag ctg ctg ggc ggc ccg tcg 1586Ser Ser Glu Ala
Asn Gly Thr Gly Leu Glu Leu Leu Gly Gly Pro Ser 435
440 445ctg cgc agc gcc tac atc acc tcc ctc tac
ttc gca ctc agc agc ctc 1634Leu Arg Ser Ala Tyr Ile Thr Ser Leu Tyr
Phe Ala Leu Ser Ser Leu 450 455
460acc agc gtg ggc ttc ggc aac gtg tcc gcc aac acg gac acc gag aag
1682Thr Ser Val Gly Phe Gly Asn Val Ser Ala Asn Thr Asp Thr Glu Lys
465 470 475atc ttc tcc atc tgc acc atg
ctc atc ggc gcc ctg atg cac gcg gtg 1730Ile Phe Ser Ile Cys Thr Met
Leu Ile Gly Ala Leu Met His Ala Val 480 485
490gtg ttt ggg aac gtg acg gcc atc atc cag cgc atg tac gcc cgc cgc
1778Val Phe Gly Asn Val Thr Ala Ile Ile Gln Arg Met Tyr Ala Arg Arg495
500 505 510ttt ctg tac cac
agc cgc acg cgc gac cag cgc gac tac atc cgc atc 1826Phe Leu Tyr His
Ser Arg Thr Arg Asp Gln Arg Asp Tyr Ile Arg Ile 515
520 525cac cgt atc ccc aag ccc ctc aag cag cgc
atg ctg gag tac ttc cag 1874His Arg Ile Pro Lys Pro Leu Lys Gln Arg
Met Leu Glu Tyr Phe Gln 530 535
540gcc acc tgg gcg gtg aac aat ggc atc gac acc acc gag ctg ctg cag
1922Ala Thr Trp Ala Val Asn Asn Gly Ile Asp Thr Thr Glu Leu Leu Gln
545 550 555agc ctc cct gac gag ctg cgc
gca gac atc gcc atg cac ctg cac aag 1970Ser Leu Pro Asp Glu Leu Arg
Ala Asp Ile Ala Met His Leu His Lys 560 565
570gag gtc ctg cag ctg cca ctg ttt gag gcg gcc agc cgc ggc tgc ctg
2018Glu Val Leu Gln Leu Pro Leu Phe Glu Ala Ala Ser Arg Gly Cys Leu575
580 585 590cgg gca ctg tct
ctg gcc ctg cgg ccc gcc ttc tgc acg ccg ggc gag 2066Arg Ala Leu Ser
Leu Ala Leu Arg Pro Ala Phe Cys Thr Pro Gly Glu 595
600 605tac ctc atc cac caa ggc gat gcc ctg cag
gcc ctc tac ttt gtc tgc 2114Tyr Leu Ile His Gln Gly Asp Ala Leu Gln
Ala Leu Tyr Phe Val Cys 610 615
620tct ggc tcc atg gag gtg ctc aag ggt ggc acc gtg ctc gcc atc cta
2162Ser Gly Ser Met Glu Val Leu Lys Gly Gly Thr Val Leu Ala Ile Leu
625 630 635ggg aag ggc gac ctg atc ggc
tgt gag ctg ccc cgg cgg gag cag gtg 2210Gly Lys Gly Asp Leu Ile Gly
Cys Glu Leu Pro Arg Arg Glu Gln Val 640 645
650gta aag gcc aat gcc gac gtg aag ggg ctg acg tac tgc gtc ctg cag
2258Val Lys Ala Asn Ala Asp Val Lys Gly Leu Thr Tyr Cys Val Leu Gln655
660 665 670tgt ctg cag ctg
gct ggc ctg cac gac agc ctt gcg ctg tac ccc gag 2306Cys Leu Gln Leu
Ala Gly Leu His Asp Ser Leu Ala Leu Tyr Pro Glu 675
680 685ttt gcc ccg cgc ttc agt cgt ggc ctc cga
ggg gag ctc agc tac aac 2354Phe Ala Pro Arg Phe Ser Arg Gly Leu Arg
Gly Glu Leu Ser Tyr Asn 690 695
700ctg ggt gct ggg gga ggc tct gca gag gtg gac acc agc tcc ctg agc
2402Leu Gly Ala Gly Gly Gly Ser Ala Glu Val Asp Thr Ser Ser Leu Ser
705 710 715ggc gac aat acc ctt atg tcc
acg ctg gag gag aag gag aca gat ggg 2450Gly Asp Asn Thr Leu Met Ser
Thr Leu Glu Glu Lys Glu Thr Asp Gly 720 725
730gag cag ggc ccc acg gtc tcc cca gcc cca gct gat gag ccc tcc agc
2498Glu Gln Gly Pro Thr Val Ser Pro Ala Pro Ala Asp Glu Pro Ser Ser735
740 745 750ccc ctg ctg tcc
cct ggc tgc acc tcc tca tcc tca gct gcc aag ctg 2546Pro Leu Leu Ser
Pro Gly Cys Thr Ser Ser Ser Ser Ala Ala Lys Leu 755
760 765cta tcc cca cgt cga aca gca ccc cgg cct
cgt cta ggt ggc aga ggg 2594Leu Ser Pro Arg Arg Thr Ala Pro Arg Pro
Arg Leu Gly Gly Arg Gly 770 775
780agg cca ggc agg gca ggg gct ttg aag gct gag gct ggc ccc tct gct
2642Arg Pro Gly Arg Ala Gly Ala Leu Lys Ala Glu Ala Gly Pro Ser Ala
785 790 795ccc cca cgg gcc cta gag ggg
cta cgg ctg ccc ccc atg cca tgg aat 2690Pro Pro Arg Ala Leu Glu Gly
Leu Arg Leu Pro Pro Met Pro Trp Asn 800 805
810gtg ccc cca gat ctg agc ccc agg gta gta gat ggc att gaa gac ggc
2738Val Pro Pro Asp Leu Ser Pro Arg Val Val Asp Gly Ile Glu Asp Gly815
820 825 830tgt ggc tcg gac
cag ccc aag ttc tct ttc cgc gtg ggc cag tct ggc 2786Cys Gly Ser Asp
Gln Pro Lys Phe Ser Phe Arg Val Gly Gln Ser Gly 835
840 845ccg gaa tgt agc agc agc ccc tcc cct gga
cca gag agc ggc ctg ctc 2834Pro Glu Cys Ser Ser Ser Pro Ser Pro Gly
Pro Glu Ser Gly Leu Leu 850 855
860act gtt ccc cat ggg ccc agc gag gca agg aac aca gac aca ctg gac
2882Thr Val Pro His Gly Pro Ser Glu Ala Arg Asn Thr Asp Thr Leu Asp
865 870 875aag ctt cgg cag gcg gtg aca
gag ctg tca gag cag gtg ctg cag atg 2930Lys Leu Arg Gln Ala Val Thr
Glu Leu Ser Glu Gln Val Leu Gln Met 880 885
890cgg gaa gga ctg cag tca ctt cgc cag gct gtg cag ctt gtc ctg gcg
2978Arg Glu Gly Leu Gln Ser Leu Arg Gln Ala Val Gln Leu Val Leu Ala895
900 905 910ccc cac agg gag
ggt ccg tgc cct cgg gca tcg gga gag ggg ccg tgc 3026Pro His Arg Glu
Gly Pro Cys Pro Arg Ala Ser Gly Glu Gly Pro Cys 915
920 925cca gcc agc acc tcc ggg ctt ctg cag cct
ctg tgt gtg gac act ggg 3074Pro Ala Ser Thr Ser Gly Leu Leu Gln Pro
Leu Cys Val Asp Thr Gly 930 935
940gca tcc tcc tac tgc ctg cag ccc cca gct ggc tct gtc ttg agt ggg
3122Ala Ser Ser Tyr Cys Leu Gln Pro Pro Ala Gly Ser Val Leu Ser Gly
945 950 955act tgg ccc cac cct cgt ccg
ggg cct cct ccc ctc atg gca ccc cgg 3170Thr Trp Pro His Pro Arg Pro
Gly Pro Pro Pro Leu Met Ala Pro Arg 960 965
970ccc tgg ggt ccc cca gcg tct cag agc tcc ccc tgg cct cga gcc aca
3218Pro Trp Gly Pro Pro Ala Ser Gln Ser Ser Pro Trp Pro Arg Ala Thr975
980 985 990gct ttc tgg acc
tcc acc tca gac tca gag ccc cct gcc tca gga gac 3266Ala Phe Trp Thr
Ser Thr Ser Asp Ser Glu Pro Pro Ala Ser Gly Asp 995
1000 1005ctc tgc tct gag ccc agc acc cct gcc tcc
cct cct cct tct gag gaa 3314Leu Cys Ser Glu Pro Ser Thr Pro Ala Ser
Pro Pro Pro Ser Glu Glu 1010 1015
1020ggg gct agg act ggg ccc gca gag cct gtg agc cag gct gag gct acc
3362Gly Ala Arg Thr Gly Pro Ala Glu Pro Val Ser Gln Ala Glu Ala Thr
1025 1030 1035agc act gga gag ccc cca cca
ggg tca ggg ggc ctg gcc ttg ccc tgg 3410Ser Thr Gly Glu Pro Pro Pro
Gly Ser Gly Gly Leu Ala Leu Pro Trp 1040 1045
1050gac ccc cac agc ctg gag atg gtg ctt att ggc tgc cat ggc tct ggc
3458Asp Pro His Ser Leu Glu Met Val Leu Ile Gly Cys His Gly Ser
Gly1055 1060 1065 1070aca gtc
cag tgg acc cag gaa gaa ggc aca ggg gtc t gagtaccagc 3505Thr Val
Gln Trp Thr Gln Glu Glu Gly Thr Gly Val 1075
1080cctagaactc agcgttgcca ggtgtgctgc catctgctgt tcggcccaac ctcagagtga
3565aggcagggtg gcagcctccc cacggactcc atgcggcccg ctggctcagg gcagggagcc
3625tggaagcaaa ggaggacctg gctcctgact ctcagagagg ataggctgga tccctggggc
3685aggcctctcc tcggcctgct cctctgacct cccggtctcc ctctgcaggc tgggggcaga
3745ggcctgagga caaggaagag ctttgccatc ccctgcatgt gcccctgcct ctacctgtcc
3805ccaaattttt atattaaaaa aaaaaataaa ataaactaaa aaaaaaaaaa aa
3857201082PRTH. sapiens 20Met Pro Ala Met Arg Gly Leu Leu Ala Pro Gln Asn
Thr Phe Leu Asp1 5 10
15Thr Ile Ala Thr Arg Phe Asp Gly Thr His Ser Asn Phe Val Leu Gly
20 25 30Asn Ala Ser Gly Gly Ala Leu
Pro Val Val Tyr Cys Ser Asp Gly Phe 35 40
45Cys Asp Leu Thr Gly Phe Ser Arg Ala Glu Val Met Gln Arg Gly
Cys 50 55 60Ala Cys Ser Phe Leu Tyr
Gly Pro Asp Thr Ser Glu Leu Val Arg Gln65 70
75 80Gln Ile Arg Lys Ala Leu Asp Glu His Lys Glu
Phe Lys Ala Glu Leu 85 90
95Ile Leu Tyr Arg Lys Ser Gly Leu Pro Phe Trp Cys Leu Leu Asp Val
100 105 110Ile Pro Ile Lys Asn Glu
Lys Gly Glu Val Ala Leu Phe Leu Val Ser 115 120
125His Lys Asp Ile Ser Glu Thr Lys Asn Arg Gly Gly Pro Asp
Arg Trp 130 135 140Lys Glu Thr Gly Gly
Gly Arg Arg Arg Tyr Gly Arg Ala Arg Ser Lys145 150
155 160Gly Phe Asn Ala Asn Arg Arg Arg Ser Arg
Ala Val Leu Tyr His Leu 165 170
175Ser Gly His Leu Gln Lys Gln Pro Lys Gly Lys His Lys Leu Asn Lys
180 185 190Gly Val Phe Gly Glu
Lys Pro Asn Leu Pro Glu Tyr Lys Val Ala Ala 195
200 205Ile Arg Lys Ser Pro Phe Ile Leu Leu His Cys Gly
Ala Leu Arg Ala 210 215 220Thr Trp Asp
Gly Phe Ile Leu Leu Ala Thr Leu Tyr Val Ala Val Thr225
230 235 240Val Pro Tyr Ser Val Cys Val
Ser Thr Ala Arg Glu Pro Ser Ala Ala 245
250 255Arg Gly Pro Pro Ser Val Cys Asp Leu Ala Val Glu
Val Leu Phe Ile 260 265 270Leu
Asp Ile Val Leu Asn Phe Arg Thr Thr Phe Val Ser Lys Ser Gly 275
280 285Gln Val Val Phe Ala Pro Lys Ser Ile
Cys Leu His Tyr Val Thr Thr 290 295
300Trp Phe Leu Leu Asp Val Ile Ala Ala Leu Pro Phe Asp Leu Leu His305
310 315 320Ala Phe Lys Val
Asn Val Tyr Phe Gly Ala His Leu Leu Lys Thr Val 325
330 335Arg Leu Leu Arg Leu Leu Arg Leu Leu Pro
Arg Leu Asp Arg Tyr Ser 340 345
350Gln Tyr Ser Ala Val Val Leu Thr Leu Leu Met Ala Val Phe Ala Leu
355 360 365Leu Ala His Trp Val Ala Cys
Val Trp Phe Tyr Ile Gly Gln Arg Glu 370 375
380Ile Glu Ser Ser Glu Ser Glu Leu Pro Glu Ile Gly Trp Leu Gln
Glu385 390 395 400Leu Ala
Arg Arg Leu Glu Thr Pro Tyr Tyr Leu Val Gly Arg Arg Pro
405 410 415Ala Gly Gly Asn Ser Ser Gly
Gln Ser Asp Asn Cys Ser Ser Ser Ser 420 425
430Glu Ala Asn Gly Thr Gly Leu Glu Leu Leu Gly Gly Pro Ser
Leu Arg 435 440 445Ser Ala Tyr Ile
Thr Ser Leu Tyr Phe Ala Leu Ser Ser Leu Thr Ser 450
455 460Val Gly Phe Gly Asn Val Ser Ala Asn Thr Asp Thr
Glu Lys Ile Phe465 470 475
480Ser Ile Cys Thr Met Leu Ile Gly Ala Leu Met His Ala Val Val Phe
485 490 495Gly Asn Val Thr Ala
Ile Ile Gln Arg Met Tyr Ala Arg Arg Phe Leu 500
505 510Tyr His Ser Arg Thr Arg Asp Gln Arg Asp Tyr Ile
Arg Ile His Arg 515 520 525Ile Pro
Lys Pro Leu Lys Gln Arg Met Leu Glu Tyr Phe Gln Ala Thr 530
535 540Trp Ala Val Asn Asn Gly Ile Asp Thr Thr Glu
Leu Leu Gln Ser Leu545 550 555
560Pro Asp Glu Leu Arg Ala Asp Ile Ala Met His Leu His Lys Glu Val
565 570 575Leu Gln Leu Pro
Leu Phe Glu Ala Ala Ser Arg Gly Cys Leu Arg Ala 580
585 590Leu Ser Leu Ala Leu Arg Pro Ala Phe Cys Thr
Pro Gly Glu Tyr Leu 595 600 605Ile
His Gln Gly Asp Ala Leu Gln Ala Leu Tyr Phe Val Cys Ser Gly 610
615 620Ser Met Glu Val Leu Lys Gly Gly Thr Val
Leu Ala Ile Leu Gly Lys625 630 635
640Gly Asp Leu Ile Gly Cys Glu Leu Pro Arg Arg Glu Gln Val Val
Lys 645 650 655Ala Asn Ala
Asp Val Lys Gly Leu Thr Tyr Cys Val Leu Gln Cys Leu 660
665 670Gln Leu Ala Gly Leu His Asp Ser Leu Ala
Leu Tyr Pro Glu Phe Ala 675 680
685Pro Arg Phe Ser Arg Gly Leu Arg Gly Glu Leu Ser Tyr Asn Leu Gly 690
695 700Ala Gly Gly Gly Ser Ala Glu Val
Asp Thr Ser Ser Leu Ser Gly Asp705 710
715 720Asn Thr Leu Met Ser Thr Leu Glu Glu Lys Glu Thr
Asp Gly Glu Gln 725 730
735Gly Pro Thr Val Ser Pro Ala Pro Ala Asp Glu Pro Ser Ser Pro Leu
740 745 750Leu Ser Pro Gly Cys Thr
Ser Ser Ser Ser Ala Ala Lys Leu Leu Ser 755 760
765Pro Arg Arg Thr Ala Pro Arg Pro Arg Leu Gly Gly Arg Gly
Arg Pro 770 775 780Gly Arg Ala Gly Ala
Leu Lys Ala Glu Ala Gly Pro Ser Ala Pro Pro785 790
795 800Arg Ala Leu Glu Gly Leu Arg Leu Pro Pro
Met Pro Trp Asn Val Pro 805 810
815Pro Asp Leu Ser Pro Arg Val Val Asp Gly Ile Glu Asp Gly Cys Gly
820 825 830Ser Asp Gln Pro Lys
Phe Ser Phe Arg Val Gly Gln Ser Gly Pro Glu 835
840 845Cys Ser Ser Ser Pro Ser Pro Gly Pro Glu Ser Gly
Leu Leu Thr Val 850 855 860Pro His Gly
Pro Ser Glu Ala Arg Asn Thr Asp Thr Leu Asp Lys Leu865
870 875 880Arg Gln Ala Val Thr Glu Leu
Ser Glu Gln Val Leu Gln Met Arg Glu 885
890 895Gly Leu Gln Ser Leu Arg Gln Ala Val Gln Leu Val
Leu Ala Pro His 900 905 910Arg
Glu Gly Pro Cys Pro Arg Ala Ser Gly Glu Gly Pro Cys Pro Ala 915
920 925Ser Thr Ser Gly Leu Leu Gln Pro Leu
Cys Val Asp Thr Gly Ala Ser 930 935
940Ser Tyr Cys Leu Gln Pro Pro Ala Gly Ser Val Leu Ser Gly Thr Trp945
950 955 960Pro His Pro Arg
Pro Gly Pro Pro Pro Leu Met Ala Pro Arg Pro Trp 965
970 975Gly Pro Pro Ala Ser Gln Ser Ser Pro Trp
Pro Arg Ala Thr Ala Phe 980 985
990Trp Thr Ser Thr Ser Asp Ser Glu Pro Pro Ala Ser Gly Asp Leu Cys
995 1000 1005Ser Glu Pro Ser Thr Pro Ala
Ser Pro Pro Pro Ser Glu Glu Gly Ala 1010 1015
1020Arg Thr Gly Pro Ala Glu Pro Val Ser Gln Ala Glu Ala Thr Ser
Thr1025 1030 1035 1040Gly
Glu Pro Pro Pro Gly Ser Gly Gly Leu Ala Leu Pro Trp Asp Pro
1045 1050 1055His Ser Leu Glu Met Val Leu
Ile Gly Cys His Gly Ser Gly Thr Val 1060 1065
1070Gln Trp Thr Gln Glu Glu Gly Thr Gly Val 1075
1080211800DNAH. sapiensCDS(346)...(1057)K+Hnov28, splice 1
21atttgaatga ctgggttact tcctagactc ttcctccttc tcttaagtac agtatagttc
60tttctctgaa aatcttcagt ctcttagttc cagatgggtt ctctatggta ggaatacagg
120acatgtagaa ggccctaggg gaatgctttc ttccccagat ctttgccctg tagtaggttt
180cagctgagca aggacgagta gtttttctgg tgtttggcct cctctgttgg gtggaaaaag
240actttcttct ctattttcct agttatatat gctatcatat gtctgttttt ctcctcttga
300agtttccctg aaacctgggc tcttgaagac gcatcactgg agcag atg gat aat gga
357Met Asp Asn Gly1gac tgg ggc tat atg atg act gac cca gtc aca tta aat
gta ggt gga 405Asp Trp Gly Tyr Met Met Thr Asp Pro Val Thr Leu Asn
Val Gly Gly5 10 15
20cac ttg tat aca acg tct ctc acc aca ttg acg cgt tac ccg gat tcc
453His Leu Tyr Thr Thr Ser Leu Thr Thr Leu Thr Arg Tyr Pro Asp Ser
25 30 35atg ctt gga gct atg ttt
ggg ggg gac ttc ccc aca gct cga gac cct 501Met Leu Gly Ala Met Phe
Gly Gly Asp Phe Pro Thr Ala Arg Asp Pro 40 45
50caa ggc aat tac ttt att gat cga gat gga cct ctt ttc
cga tat gtc 549Gln Gly Asn Tyr Phe Ile Asp Arg Asp Gly Pro Leu Phe
Arg Tyr Val 55 60 65ctc aac ttc
tta aga act tca gaa ttg acc tta ccg ttg gat ttt aag 597Leu Asn Phe
Leu Arg Thr Ser Glu Leu Thr Leu Pro Leu Asp Phe Lys 70
75 80gaa ttt gat ctg ctt cgg aaa gaa gca gat ttt tac
cag att gag ccc 645Glu Phe Asp Leu Leu Arg Lys Glu Ala Asp Phe Tyr
Gln Ile Glu Pro85 90 95
100ttg att cag tgt ctc aat gat cct aag cct ttg tat ccc atg gat act
693Leu Ile Gln Cys Leu Asn Asp Pro Lys Pro Leu Tyr Pro Met Asp Thr
105 110 115ttt gaa gaa gtt gtg
gag ctg tct agt act cgg aag ctt tct aag tac 741Phe Glu Glu Val Val
Glu Leu Ser Ser Thr Arg Lys Leu Ser Lys Tyr 120
125 130tcc aac cca gtg gct gtc atc ata acg caa cta acc
atc acc act aag 789Ser Asn Pro Val Ala Val Ile Ile Thr Gln Leu Thr
Ile Thr Thr Lys 135 140 145gtc cat
tcc tta cta gaa ggc atc tca aat tat ttt acc aag tgg aat 837Val His
Ser Leu Leu Glu Gly Ile Ser Asn Tyr Phe Thr Lys Trp Asn 150
155 160aag cac atg atg gac acc aga gac tgc cag gtt
tcc ttt act ttt gga 885Lys His Met Met Asp Thr Arg Asp Cys Gln Val
Ser Phe Thr Phe Gly165 170 175
180ccc tgt gat tat cac cag gaa gtt tct ctt agg gtc cac ctg atg gaa
933Pro Cys Asp Tyr His Gln Glu Val Ser Leu Arg Val His Leu Met Glu
185 190 195tac att aca aaa caa
ggt ttc acg atc cgc aac acc cgg gtg cat cac 981Tyr Ile Thr Lys Gln
Gly Phe Thr Ile Arg Asn Thr Arg Val His His 200
205 210atg agt gag cgg gcc aat gaa aac aca gtg gag cac
aac tgg act ttc 1029Met Ser Glu Arg Ala Asn Glu Asn Thr Val Glu His
Asn Trp Thr Phe 215 220 225tgt agg
cta gcc cgg aag aca gac gac t gatctccgac cctgccacag 1077Cys Arg
Leu Ala Arg Lys Thr Asp Asp 230 235gttcctggaa
agactctcca ggaaatggaa gatactgatt ttttttttta aatcacagtg 1137tgagatattt
tttttctttt aaatagttgt atttatttga aggcagtgag gaccagaagg 1197aagttttgtg
ctttggcaga ctcctccatg ttttgttccc ttccccctga gtatgcatgt 1257gcctgttcag
agtctccaga tacctttttt ataaaaagaa gtctgaaaat cattatggta 1317tataatctac
ccttaacaga gcttttctta ttacagtgct aaaatgattt ctgataaaat 1377ggtccctaac
tcaactagaa ggctaaaaat acaagaatga aagaataagc agagtactca 1437tgatgccttt
gagaaaaatc aaaacatcat gtagggtgac ctagtttcca aaccaataaa 1497taagtagtat
tgtaatatta aaggaaaact gttccaatca tttaaaagta cttattaagt 1557actgcttttt
acagttatga caactgtttc tttctatgca tataaatcaa ggaaccaaat 1617atctgtagcc
atggaaatgt ctgactagaa atatttatat tgaattctga atacaaaatg 1677tccctgtggt
agaaaactta ctctttatgc ctggtgcagt ataattccca agtgtactgt 1737ctaccagaaa
aaaaaaacaa aactaataaa aaatgaaata tgaaaaaaaa aaaaaaaaaa 1797aaa
1800221836DNAH.
sapiensCDS(382)...(1093)K+Hnov28 splice 2 22gaggaatgtt atgattttgt
gactatttgt gacagctttt taatattagg tcacttttaa 60acctatagct tctctcttct
agaccacatg gttgggaaag gagaaagaga aaatgattac 120ttgtagagaa aaatccattt
ctgcagtggt atggttaagg ataatctaac cataatcaca 180ttatccttgt atgcctggct
acttgtgctg gcctgtatgt gaatgttaac cccaaagact 240cctttagatg tcgctgaact
agttactata aaaagtattt cgctttcaaa ctcccacatt 300tcaagaagag caaaactcaa
tacaaggcaa ttttgaagtt tccctgaaac ctgggctctt 360gaagacgcat cactggagca g
atg gat aat gga gac tgg ggc tat atg atg 411Met Asp Asn Gly Asp Trp
Gly Tyr Met Met1 5 10act gac cca gtc aca
tta aat gta ggt gga cac ttg tat aca acg tct 459Thr Asp Pro Val Thr
Leu Asn Val Gly Gly His Leu Tyr Thr Thr Ser 15
20 25ctc acc aca ttg acg cgt tac ccg gat tcc atg ctt
gga gct atg ttt 507Leu Thr Thr Leu Thr Arg Tyr Pro Asp Ser Met Leu
Gly Ala Met Phe 30 35 40ggg ggg
gac ttc ccc aca gct cga gac cct caa ggc aat tac ttt att 555Gly Gly
Asp Phe Pro Thr Ala Arg Asp Pro Gln Gly Asn Tyr Phe Ile 45
50 55gat cga gat gga cct ctt ttc cga tat gtc ctc
aac ttc tta aga act 603Asp Arg Asp Gly Pro Leu Phe Arg Tyr Val Leu
Asn Phe Leu Arg Thr60 65 70tca gaa ttg
acc tta ccg ttg gat ttt aag gaa ttt gat ctg ctt cgg 651Ser Glu Leu
Thr Leu Pro Leu Asp Phe Lys Glu Phe Asp Leu Leu Arg 75
80 85 90aaa gaa gca gat
ttt tac cag att gag ccc ttg att cag tgt ctc aat 699Lys Glu Ala Asp
Phe Tyr Gln Ile Glu Pro Leu Ile Gln Cys Leu Asn 95
100 105gat cct aag cct ttg tat ccc atg gat act ttt
gaa gaa gtt gtg gag 747Asp Pro Lys Pro Leu Tyr Pro Met Asp Thr Phe
Glu Glu Val Val Glu 110 115 120ctg
tct agt act cgg aag ctt tct aag tac tcc aac cca gtg gct gtc 795Leu
Ser Ser Thr Arg Lys Leu Ser Lys Tyr Ser Asn Pro Val Ala Val 125
130 135atc ata acg caa cta acc atc acc act aag
gtc cat tcc tta cta gaa 843Ile Ile Thr Gln Leu Thr Ile Thr Thr Lys
Val His Ser Leu Leu Glu140 145 150ggc atc
tca aat tat ttt acc aag tgg aat aag cac atg atg gac acc 891Gly Ile
Ser Asn Tyr Phe Thr Lys Trp Asn Lys His Met Met Asp Thr
155 160 165 170aga gac
tgc cag gtt tcc ttt act ttt gga ccc tgt gat tat cac cag 939Arg Asp
Cys Gln Val Ser Phe Thr Phe Gly Pro Cys Asp Tyr His Gln 175
180 185gaa gtt tct ctt agg gtc cac ctg atg
gaa tac att aca aaa caa ggt 987Glu Val Ser Leu Arg Val His Leu Met
Glu Tyr Ile Thr Lys Gln Gly 190 195
200ttc acg atc cgc aac acc cgg gtg cat cac atg agt gag cgg gcc aat
1035Phe Thr Ile Arg Asn Thr Arg Val His His Met Ser Glu Arg Ala Asn
205 210 215gaa aac aca gtg gag cac aac
tgg act ttc tgt agg cta gcc cgg aag 1083Glu Asn Thr Val Glu His Asn
Trp Thr Phe Cys Arg Leu Ala Arg Lys220 225
230aca gac gac t gatctccgac cctgccacag gttcctggaa agactctcca
1133Thr Asp Asp235ggaaatggaa gatactgatt ttttttttta aatcacagtg tgagatattt
tttttctttt 1193aaatagttgt atttatttga aggcagtgag gaccagaagg aagttttgtg
ctttggcaga 1253ctcctccatg ttttgttccc ttccccctga gtatgcatgt gcctgttcag
agtctccaga 1313tacctttttt ataaaaagaa gtctgaaaat cattatggta tataatctac
ccttaacaga 1373gcttttctta ttacagtgct aaaatgattt ctgataaaat ggtccctaac
tcaactagaa 1433ggctaaaaat acaagaatga aagaataagc agagtactca tgatgccttt
gagaaaaatc 1493aaaacatcat gtagggtgac ctagtttcca aaccaataaa taagtagtat
tgtaatatta 1553aaggaaaact gttccaatca tttaaaagta cttattaagt actgcttttt
acagttatga 1613caactgtttc tttctatgca tataaatcaa ggaaccaaat atctgtagcc
atggaaatgt 1673ctgactagaa atatttatat tgaattctga atacaaaatg tccctgtggt
agaaaactta 1733ctctttatgc ctggtgcagt ataattccca agtgtactgt ctaccagaaa
aaaaaaacaa 1793aactaataaa aaatgaaata tgaaaaaaaa aaaaaaaaaa aaa
1836231751DNAH. sapiensCDS(297)...(1008)K+Hnov28 splice 3
23ccatgtttct taccatgtct tgccagagct ttagaaattt gctctgcagt ttgctttaca
60ggttgatttg ggattgaagt gtgtgagagg gaactgacta aggcagttca gtagctggga
120aactgtttgt ttaaatgctt ttgaattgta gataaaaata aattcacatt ggcatcatta
180gtatctgagc atttctcagt gtcttaaggc tggctctcca tgagtgctgg ctgattgact
240ctcatctata tcgtttccct gaaacctggg ctcttgaaga cgcatcactg gagcag atg
299Met1gat aat gga gac tgg ggc tat atg atg act gac cca gtc aca tta aat
347Asp Asn Gly Asp Trp Gly Tyr Met Met Thr Asp Pro Val Thr Leu Asn
5 10 15gta ggt gga cac ttg tat
aca acg tct ctc acc aca ttg acg cgt tac 395Val Gly Gly His Leu Tyr
Thr Thr Ser Leu Thr Thr Leu Thr Arg Tyr 20 25
30ccg gat tcc atg ctt gga gct atg ttt ggg ggg gac ttc ccc
aca gct 443Pro Asp Ser Met Leu Gly Ala Met Phe Gly Gly Asp Phe Pro
Thr Ala 35 40 45cga gac cct caa ggc
aat tac ttt att gat cga gat gga cct ctt ttc 491Arg Asp Pro Gln Gly
Asn Tyr Phe Ile Asp Arg Asp Gly Pro Leu Phe50 55
60 65cga tat gtc ctc aac ttc tta aga act tca
gaa ttg acc tta ccg ttg 539Arg Tyr Val Leu Asn Phe Leu Arg Thr Ser
Glu Leu Thr Leu Pro Leu 70 75
80gat ttt aag gaa ttt gat ctg ctt cgg aaa gaa gca gat ttt tac cag
587Asp Phe Lys Glu Phe Asp Leu Leu Arg Lys Glu Ala Asp Phe Tyr Gln
85 90 95att gag ccc ttg att cag
tgt ctc aat gat cct aag cct ttg tat ccc 635Ile Glu Pro Leu Ile Gln
Cys Leu Asn Asp Pro Lys Pro Leu Tyr Pro 100 105
110atg gat act ttt gaa gaa gtt gtg gag ctg tct agt act cgg
aag ctt 683Met Asp Thr Phe Glu Glu Val Val Glu Leu Ser Ser Thr Arg
Lys Leu 115 120 125tct aag tac tcc aac
cca gtg gct gtc atc ata acg caa cta acc atc 731Ser Lys Tyr Ser Asn
Pro Val Ala Val Ile Ile Thr Gln Leu Thr Ile130 135
140 145acc act aag gtc cat tcc tta cta gaa ggc
atc tca aat tat ttt acc 779Thr Thr Lys Val His Ser Leu Leu Glu Gly
Ile Ser Asn Tyr Phe Thr 150 155
160aag tgg aat aag cac atg atg gac acc aga gac tgc cag gtt tcc ttt
827Lys Trp Asn Lys His Met Met Asp Thr Arg Asp Cys Gln Val Ser Phe
165 170 175act ttt gga ccc tgt gat
tat cac cag gaa gtt tct ctt agg gtc cac 875Thr Phe Gly Pro Cys Asp
Tyr His Gln Glu Val Ser Leu Arg Val His 180 185
190ctg atg gaa tac att aca aaa caa ggt ttc acg atc cgc aac
acc cgg 923Leu Met Glu Tyr Ile Thr Lys Gln Gly Phe Thr Ile Arg Asn
Thr Arg 195 200 205gtg cat cac atg agt
gag cgg gcc aat gaa aac aca gtg gag cac aac 971Val His His Met Ser
Glu Arg Ala Asn Glu Asn Thr Val Glu His Asn210 215
220 225tgg act ttc tgt agg cta gcc cgg aag aca
gac gac t gatctccgac 1018Trp Thr Phe Cys Arg Leu Ala Arg Lys Thr
Asp Asp 230 235cctgccacag gttcctggaa
agactctcca ggaaatggaa gatactgatt ttttttttta 1078aatcacagtg tgagatattt
tttttctttt aaatagttgt atttatttga aggcagtgag 1138gaccagaagg aagttttgtg
ctttggcaga ctcctccatg ttttgttccc ttccccctga 1198gtatgcatgt gcctgttcag
agtctccaga tacctttttt ataaaaagaa gtctgaaaat 1258cattatggta tataatctac
ccttaacaga gcttttctta ttacagtgct aaaatgattt 1318ctgataaaat ggtccctaac
tcaactagaa ggctaaaaat acaagaatga aagaataagc 1378agagtactca tgatgccttt
gagaaaaatc aaaacatcat gtagggtgac ctagtttcca 1438aaccaataaa taagtagtat
tgtaatatta aaggaaaact gttccaatca tttaaaagta 1498cttattaagt actgcttttt
acagttatga caactgtttc tttctatgca tataaatcaa 1558ggaaccaaat atctgtagcc
atggaaatgt ctgactagaa atatttatat tgaattctga 1618atacaaaatg tccctgtggt
agaaaactta ctctttatgc ctggtgcagt ataattccca 1678agtgtactgt ctaccagaaa
aaaaaaacaa aactaataaa aaatgaaata tgaaaaaaaa 1738aaaaaaaaaa aaa
1751241542DNAH.
sapiensCDS(88)...(799)K+Hnov28, splice 4 24cgggcatctc ccggcccggc
cgcagcagcc gccgccgccg cgcatttccc tgaaacctgg 60gctcttgaag acgcatcact
ggagcag atg gat aat gga gac tgg ggc tat atg 114Met Asp Asn Gly Asp Trp
Gly Tyr Met1 5atg act gac cca gtc aca tta aat gta ggt gga
cac ttg tat aca acg 162Met Thr Asp Pro Val Thr Leu Asn Val Gly Gly
His Leu Tyr Thr Thr10 15 20
25tct ctc acc aca ttg acg cgt tac ccg gat tcc atg ctt gga gct atg
210Ser Leu Thr Thr Leu Thr Arg Tyr Pro Asp Ser Met Leu Gly Ala Met
30 35 40ttt ggg ggg gac ttc
ccc aca gct cga gac cct caa ggc aat tac ttt 258Phe Gly Gly Asp Phe
Pro Thr Ala Arg Asp Pro Gln Gly Asn Tyr Phe 45
50 55att gat cga gat gga cct ctt ttc cga tat gtc ctc
aac ttc tta aga 306Ile Asp Arg Asp Gly Pro Leu Phe Arg Tyr Val Leu
Asn Phe Leu Arg 60 65 70act tca
gaa ttg acc tta ccg ttg gat ttt aag gaa ttt gat ctg ctt 354Thr Ser
Glu Leu Thr Leu Pro Leu Asp Phe Lys Glu Phe Asp Leu Leu 75
80 85cgg aaa gaa gca gat ttt tac cag att gag ccc
ttg att cag tgt ctc 402Arg Lys Glu Ala Asp Phe Tyr Gln Ile Glu Pro
Leu Ile Gln Cys Leu90 95 100
105aat gat cct aag cct ttg tat ccc atg gat act ttt gaa gaa gtt gtg
450Asn Asp Pro Lys Pro Leu Tyr Pro Met Asp Thr Phe Glu Glu Val Val
110 115 120gag ctg tct agt act
cgg aag ctt tct aag tac tcc aac cca gtg gct 498Glu Leu Ser Ser Thr
Arg Lys Leu Ser Lys Tyr Ser Asn Pro Val Ala 125
130 135gtc atc ata acg caa cta acc atc acc act aag gtc
cat tcc tta cta 546Val Ile Ile Thr Gln Leu Thr Ile Thr Thr Lys Val
His Ser Leu Leu 140 145 150gaa ggc
atc tca aat tat ttt acc aag tgg aat aag cac atg atg gac 594Glu Gly
Ile Ser Asn Tyr Phe Thr Lys Trp Asn Lys His Met Met Asp 155
160 165acc aga gac tgc cag gtt tcc ttt act ttt gga
ccc tgt gat tat cac 642Thr Arg Asp Cys Gln Val Ser Phe Thr Phe Gly
Pro Cys Asp Tyr His170 175 180
185cag gaa gtt tct ctt agg gtc cac ctg atg gaa tac att aca aaa caa
690Gln Glu Val Ser Leu Arg Val His Leu Met Glu Tyr Ile Thr Lys Gln
190 195 200ggt ttc acg atc cgc
aac acc cgg gtg cat cac atg agt gag cgg gcc 738Gly Phe Thr Ile Arg
Asn Thr Arg Val His His Met Ser Glu Arg Ala 205
210 215aat gaa aac aca gtg gag cac aac tgg act ttc tgt
agg cta gcc cgg 786Asn Glu Asn Thr Val Glu His Asn Trp Thr Phe Cys
Arg Leu Ala Arg 220 225 230aag aca
gac gac t gatctccgac cctgccacag gttcctggaa agactctcca 839Lys Thr
Asp Asp 235ggaaatggaa gatactgatt ttttttttta aatcacagtg tgagatattt
tttttctttt 899aaatagttgt atttatttga aggcagtgag gaccagaagg aagttttgtg
ctttggcaga 959ctcctccatg ttttgttccc ttccccctga gtatgcatgt gcctgttcag
agtctccaga 1019tacctttttt ataaaaagaa gtctgaaaat cattatggta tataatctac
ccttaacaga 1079gcttttctta ttacagtgct aaaatgattt ctgataaaat ggtccctaac
tcaactagaa 1139ggctaaaaat acaagaatga aagaataagc agagtactca tgatgccttt
gagaaaaatc 1199aaaacatcat gtagggtgac ctagtttcca aaccaataaa taagtagtat
tgtaatatta 1259aaggaaaact gttccaatca tttaaaagta cttattaagt actgcttttt
acagttatga 1319caactgtttc tttctatgca tataaatcaa ggaaccaaat atctgtagcc
atggaaatgt 1379ctgactagaa atatttatat tgaattctga atacaaaatg tccctgtggt
agaaaactta 1439ctctttatgc ctggtgcagt ataattccca agtgtactgt ctaccagaaa
aaaaaaacaa 1499aactaataaa aaatgaaata tgaaaaaaaa aaaaaaaaaa aaa
154225237PRTH. sapiens 25Met Asp Asn Gly Asp Trp Gly Tyr Met
Met Thr Asp Pro Val Thr Leu1 5 10
15Asn Val Gly Gly His Leu Tyr Thr Thr Ser Leu Thr Thr Leu Thr Arg
20 25 30Tyr Pro Asp Ser Met
Leu Gly Ala Met Phe Gly Gly Asp Phe Pro Thr 35 40
45Ala Arg Asp Pro Gln Gly Asn Tyr Phe Ile Asp Arg Asp
Gly Pro Leu 50 55 60Phe Arg Tyr Val
Leu Asn Phe Leu Arg Thr Ser Glu Leu Thr Leu Pro65 70
75 80Leu Asp Phe Lys Glu Phe Asp Leu Leu
Arg Lys Glu Ala Asp Phe Tyr 85 90
95Gln Ile Glu Pro Leu Ile Gln Cys Leu Asn Asp Pro Lys Pro Leu
Tyr 100 105 110Pro Met Asp Thr
Phe Glu Glu Val Val Glu Leu Ser Ser Thr Arg Lys 115
120 125Leu Ser Lys Tyr Ser Asn Pro Val Ala Val Ile Ile
Thr Gln Leu Thr 130 135 140Ile Thr Thr
Lys Val His Ser Leu Leu Glu Gly Ile Ser Asn Tyr Phe145
150 155 160Thr Lys Trp Asn Lys His Met
Met Asp Thr Arg Asp Cys Gln Val Ser 165
170 175Phe Thr Phe Gly Pro Cys Asp Tyr His Gln Glu Val
Ser Leu Arg Val 180 185 190His
Leu Met Glu Tyr Ile Thr Lys Gln Gly Phe Thr Ile Arg Asn Thr 195
200 205Arg Val His His Met Ser Glu Arg Ala
Asn Glu Asn Thr Val Glu His 210 215
220Asn Trp Thr Phe Cys Arg Leu Ala Arg Lys Thr Asp Asp225
230 235263204DNAH. sapiensCDS(182)...(1349)K+Hnov42
26cggccgaacc ttgggtgtgg gacagagtgc gtgcgtgtgg tgtgtcccca agggcaggaa
60ggtggcgaag ggaggcgaat ccgagtgggt ggagggaggg gaagggcggg aggagaaaaa
120ggtgggagga ggaccaggtg ggagggtggc ggctcactca ggacccagcg ggggcagcgc
180g atg agg cgg gtg acc ctg ttc ctg aac ggc agc ccc aag aac gga aag
229Met Arg Arg Val Thr Leu Phe Leu Asn Gly Ser Pro Lys Asn Gly Lys1
5 10 15gtg gtt gct gta tat gga
act tta tct gat ttg ctt tct gtg gcc agc 277Val Val Ala Val Tyr Gly
Thr Leu Ser Asp Leu Leu Ser Val Ala Ser 20 25
30agt aaa ctc ggc ata aaa gcc acc agt gtg tat aat ggg
aaa ggt gga 325Ser Lys Leu Gly Ile Lys Ala Thr Ser Val Tyr Asn Gly
Lys Gly Gly 35 40 45ctg att gat
gat att gct ttg atc agg gat gat gat gtt ttg ttt gtt 373Leu Ile Asp
Asp Ile Ala Leu Ile Arg Asp Asp Asp Val Leu Phe Val 50
55 60tgt gaa gga gag cca ttt att gat cct cag aca gat
tct aag cct cct 421Cys Glu Gly Glu Pro Phe Ile Asp Pro Gln Thr Asp
Ser Lys Pro Pro65 70 75
80gag gga ttg tta gga ttc cac aca gac tgg ctg aca tta aat gtt gga
469Glu Gly Leu Leu Gly Phe His Thr Asp Trp Leu Thr Leu Asn Val Gly
85 90 95ggg cgg tac ttt aca act
aca cgg agc act tta gtg aat aaa gaa cct 517Gly Arg Tyr Phe Thr Thr
Thr Arg Ser Thr Leu Val Asn Lys Glu Pro 100
105 110gac agt atg ctg gcc cac atg ttt aag gac aaa ggt
gtc tgg gga aat 565Asp Ser Met Leu Ala His Met Phe Lys Asp Lys Gly
Val Trp Gly Asn 115 120 125aag caa
gat cat aga gga gct ttc tta att gac cga agt cct gag tac 613Lys Gln
Asp His Arg Gly Ala Phe Leu Ile Asp Arg Ser Pro Glu Tyr 130
135 140ttc gaa ccc att ttg aac tac ttg cgt cat gga
cag ctc att gta aat 661Phe Glu Pro Ile Leu Asn Tyr Leu Arg His Gly
Gln Leu Ile Val Asn145 150 155
160gat ggc att aat tta ttg ggt gtg tta gaa gaa gca aga ttt ttt ggt
709Asp Gly Ile Asn Leu Leu Gly Val Leu Glu Glu Ala Arg Phe Phe Gly
165 170 175att gac tca ttg att
gaa cac cta gaa gtg gca ata aag aat tct caa 757Ile Asp Ser Leu Ile
Glu His Leu Glu Val Ala Ile Lys Asn Ser Gln 180
185 190cca ccg gag gat cat tca cca ata tcc cga aag gaa
ttt gtc cga ttt 805Pro Pro Glu Asp His Ser Pro Ile Ser Arg Lys Glu
Phe Val Arg Phe 195 200 205ttg cta
gca act cca acc aag tca gaa ctg cga tgc cag ggt ttg aac 853Leu Leu
Ala Thr Pro Thr Lys Ser Glu Leu Arg Cys Gln Gly Leu Asn 210
215 220ttc agt ggt gct gat ctt tct cgt ttg gac ctt
cga tac att aac ttc 901Phe Ser Gly Ala Asp Leu Ser Arg Leu Asp Leu
Arg Tyr Ile Asn Phe225 230 235
240aaa atg gcc aat tta agc cgc tgt aat ctt gca cat gca aat ctt tgc
949Lys Met Ala Asn Leu Ser Arg Cys Asn Leu Ala His Ala Asn Leu Cys
245 250 255tgt gca aat ctt gaa
cga gct gat ctc tct gga tca gtg ctt gac tgt 997Cys Ala Asn Leu Glu
Arg Ala Asp Leu Ser Gly Ser Val Leu Asp Cys 260
265 270gcg aat ctc cag gga gtc aag atg ctc tgt tct aat
gca gaa gga gca 1045Ala Asn Leu Gln Gly Val Lys Met Leu Cys Ser Asn
Ala Glu Gly Ala 275 280 285tcc ctg
aaa ctg tgt aat ttt gag gat cct tct ggt ctt aaa gcc aat 1093Ser Leu
Lys Leu Cys Asn Phe Glu Asp Pro Ser Gly Leu Lys Ala Asn 290
295 300tta gaa ggt gct aat ctg aaa ggt gtg gat atg
gaa gga agt cag atg 1141Leu Glu Gly Ala Asn Leu Lys Gly Val Asp Met
Glu Gly Ser Gln Met305 310 315
320aca gga att aac ctg aga gtg gct acc tta aaa aat gca aag ttg aag
1189Thr Gly Ile Asn Leu Arg Val Ala Thr Leu Lys Asn Ala Lys Leu Lys
325 330 335aac tgt aac ctc aga
gga gca act ctg gca gga act gat tta gag aat 1237Asn Cys Asn Leu Arg
Gly Ala Thr Leu Ala Gly Thr Asp Leu Glu Asn 340
345 350tgt gat ctg tct ggg tgt gat ctt caa gaa gcc aac
ctg aga ggg tcc 1285Cys Asp Leu Ser Gly Cys Asp Leu Gln Glu Ala Asn
Leu Arg Gly Ser 355 360 365aac gtg
aag gga gct ata ttt gaa gag atg ctg aca cca cta cac atg 1333Asn Val
Lys Gly Ala Ile Phe Glu Glu Met Leu Thr Pro Leu His Met 370
375 380tca caa agt gtc aga t gagaatttta ggggctggag
gaagatgtaa aagatgaaaa 1389Ser Gln Ser Val Arg385tgttttcctt atcacttttc
tttctccacc cactcagttg tctagaagaa ataacactgt 1449aaggaaattt taaaaaaaaa
catttagagg attatgcttg ttttgagtgg tgcataaggg 1509aaaaaactga ctttttttcc
atattctgat ttttaacaga aaagcactca tttaatagat 1569gtagggaaac tagatattgc
tgccttttga atggggtagg ggggtttacc tggttttatg 1629accaggcata gtatctatta
tatttgcttt taaataggca tgatgtggaa ataccatctt 1689ggtttgagat gcatttgagg
attttaattt atggaaagca caacatatgc aattatattt 1749attgaattcc tagatgcagt
atggatattt aaattgttaa aactttatga aaacttggaa 1809aaggttgttc aggtttataa
atagctttag tgatgcctcc cctctttaaa tacctgtcac 1869accgtatgaa tatggtgaga
tcagactccc taagactctt ttcaggttca tttttataat 1929gtttactttt taggacagaa
cagtagctaa attaaagtaa tatccagttc ttactgattg 1989agacagagtg gaaagaaaga
catcattgta catcactgtc attccaaagg tacagtgtaa 2049ctctggatgg aggaataact
tacctatcac tacaacactt acaaatgaga atttctcaga 2109atttcattct aggcaagttc
cactcaacac cagatcaagc aattctatct atttacacta 2169ttagcctagt tttctcatac
agtcatcaca agcataggaa gatacttcaa aaccaaaaaa 2229accaaggtgc atcattaata
ttcatttaat tcaaatacca aatagtttac atagggccag 2289cttagaaata gatactaaat
ccagagctac tgcaatcaaa gcttatatga gtgaatatgg 2349tagagttgcc tgctaaaagg
caatgtaata taattgcagc tagaacccta cagtggggaa 2409tgaggaattt taaacacaca
tttgattaca gccaccaaaa aaatagacgt aaaaataaag 2469gcatttggct ggtccaagat
gtaattttca atcagtcagc acctgtgatt cttttactta 2529tttttttgtg gttttttttt
tttaaacaaa ttttagccca attttcttga gtcattctct 2589ctctgcagca gcagaggaag
ggcctgtacc tccctaccaa tgacttggtg tccttatttt 2649ctaccccaag agcagggata
ttagctgtgt ccaaatgggt tctgaattct acagactcat 2709caacatgagg caaggaatca
ttgaaaacca cctgtgtctc ctttgggaga atgacatatc 2769tttagtattt acgtagctta
ttcttctata tctacatatg caaagctttc cttaacagta 2829aagggtacat atgcatagtg
ggaggagatc agacctttac aagtgaagga aagcaacttc 2889agaaatgaat tattttcttt
gctttattat ttttaccaag acagagaagt attgtattga 2949gagataatct attttcataa
tcaatatgtg cctaaattat atttaaatca tttcactctg 3009tactatattt tcaggaatta
cagaatgtgg tattcattca cttaaaggta cctctgtaga 3069aataacctaa aactgcagaa
ggatctgaaa gatctaaaca tggtgtgctt agaaactgca 3129gattttagat ctaatgtata
ctgcattaat aaatgatata aagtgtttgt tgaaaaaaaa 3189aaaaaaaaaa aaaaa
320427389PRTH. sapiens 27Met
Arg Arg Val Thr Leu Phe Leu Asn Gly Ser Pro Lys Asn Gly Lys1
5 10 15Val Val Ala Val Tyr Gly Thr Leu
Ser Asp Leu Leu Ser Val Ala Ser 20 25
30Ser Lys Leu Gly Ile Lys Ala Thr Ser Val Tyr Asn Gly Lys Gly
Gly 35 40 45Leu Ile Asp Asp Ile
Ala Leu Ile Arg Asp Asp Asp Val Leu Phe Val 50 55
60Cys Glu Gly Glu Pro Phe Ile Asp Pro Gln Thr Asp Ser Lys
Pro Pro65 70 75 80Glu
Gly Leu Leu Gly Phe His Thr Asp Trp Leu Thr Leu Asn Val Gly
85 90 95Gly Arg Tyr Phe Thr Thr Thr
Arg Ser Thr Leu Val Asn Lys Glu Pro 100 105
110Asp Ser Met Leu Ala His Met Phe Lys Asp Lys Gly Val Trp
Gly Asn 115 120 125Lys Gln Asp His
Arg Gly Ala Phe Leu Ile Asp Arg Ser Pro Glu Tyr 130
135 140Phe Glu Pro Ile Leu Asn Tyr Leu Arg His Gly Gln
Leu Ile Val Asn145 150 155
160Asp Gly Ile Asn Leu Leu Gly Val Leu Glu Glu Ala Arg Phe Phe Gly
165 170 175Ile Asp Ser Leu Ile
Glu His Leu Glu Val Ala Ile Lys Asn Ser Gln 180
185 190Pro Pro Glu Asp His Ser Pro Ile Ser Arg Lys Glu
Phe Val Arg Phe 195 200 205Leu Leu
Ala Thr Pro Thr Lys Ser Glu Leu Arg Cys Gln Gly Leu Asn 210
215 220Phe Ser Gly Ala Asp Leu Ser Arg Leu Asp Leu
Arg Tyr Ile Asn Phe225 230 235
240Lys Met Ala Asn Leu Ser Arg Cys Asn Leu Ala His Ala Asn Leu Cys
245 250 255Cys Ala Asn Leu
Glu Arg Ala Asp Leu Ser Gly Ser Val Leu Asp Cys 260
265 270Ala Asn Leu Gln Gly Val Lys Met Leu Cys Ser
Asn Ala Glu Gly Ala 275 280 285Ser
Leu Lys Leu Cys Asn Phe Glu Asp Pro Ser Gly Leu Lys Ala Asn 290
295 300Leu Glu Gly Ala Asn Leu Lys Gly Val Asp
Met Glu Gly Ser Gln Met305 310 315
320Thr Gly Ile Asn Leu Arg Val Ala Thr Leu Lys Asn Ala Lys Leu
Lys 325 330 335Asn Cys Asn
Leu Arg Gly Ala Thr Leu Ala Gly Thr Asp Leu Glu Asn 340
345 350Cys Asp Leu Ser Gly Cys Asp Leu Gln Glu
Ala Asn Leu Arg Gly Ser 355 360
365Asn Val Lys Gly Ala Ile Phe Glu Glu Met Leu Thr Pro Leu His Met 370
375 380Ser Gln Ser Val Arg385281246DNAH.
sapiensCDS(432)...(1092)K+Hnov44, splice 1 28cagaaaacca cgcaggtcct
tcttgatcat ctagaactga ccgctccgcc ttgccaggag 60tctgcagaac cacgtggcta
gcctgcctga agttctcacc tctccaggaa ggcggggggc 120ttctaatggc tgcagctgcg
ctgggggctg ggggctcccg ctgggactcc acttccgtgg 180atgtctaagc ttcacctttc
ttgcgcccgc aggggcatga ctcaggtgaa agggagccat 240tttctcagac ccctggcctc
atgcagccct tcagcatccc cgtgcaaatc acacttcagg 300gcagccggag gcgccagggg
aggacagcct ttcctgcctc agggaagaag agagagacag 360actacagtga tggagaccca
ctagatgtgc acaagaggct gccatccagt gctggagagg 420accgagccgt g atg ctg
ggg ttt gcc atg atg ggc ttc tca gtc cta atg 470Met Leu Gly Phe Ala
Met Met Gly Phe Ser Val Leu Met1 5 10ttc
ttc ttg ctc gga aca acc att cta aag cct ttt atg ctc agc att 518Phe
Phe Leu Leu Gly Thr Thr Ile Leu Lys Pro Phe Met Leu Ser Ile 15
20 25cag aga gaa gaa tcg acc tgc act gcc atc
cac aca gat atc atg gac 566Gln Arg Glu Glu Ser Thr Cys Thr Ala Ile
His Thr Asp Ile Met Asp30 35 40
45gac tgg ctg gac tgt gcc ttc acc tgt ggt gtg cac tgc cac ggt
cag 614Asp Trp Leu Asp Cys Ala Phe Thr Cys Gly Val His Cys His Gly
Gln 50 55 60ggg aag tac
ccg tgt ctt cag gtg ttt gtg aac ctc agc cat cca ggt 662Gly Lys Tyr
Pro Cys Leu Gln Val Phe Val Asn Leu Ser His Pro Gly 65
70 75cag aaa gct ctc cta cat tat aat gaa gag
gct gtc cag ata aat ccc 710Gln Lys Ala Leu Leu His Tyr Asn Glu Glu
Ala Val Gln Ile Asn Pro 80 85
90aag tgc ttt tac aca cct aag tgc cac caa gat aga aat gat ttg ctc
758Lys Cys Phe Tyr Thr Pro Lys Cys His Gln Asp Arg Asn Asp Leu Leu 95
100 105aac agt gct ctg gac ata aaa gaa ttc
ttc gat cac aaa aat gga act 806Asn Ser Ala Leu Asp Ile Lys Glu Phe
Phe Asp His Lys Asn Gly Thr110 115 120
125ccc ttt tca tgc ttc tac agt cca gcc agc caa tct gaa gat
gtc att 854Pro Phe Ser Cys Phe Tyr Ser Pro Ala Ser Gln Ser Glu Asp
Val Ile 130 135 140ctt ata
aaa aag tat gac caa atg gct atc ttc cac tgt tta ttt tgg 902Leu Ile
Lys Lys Tyr Asp Gln Met Ala Ile Phe His Cys Leu Phe Trp 145
150 155cct tca ctg act ctg cta ggt ggt gcc
ctg att gtt ggc atg gtg aga 950Pro Ser Leu Thr Leu Leu Gly Gly Ala
Leu Ile Val Gly Met Val Arg 160 165
170tta aca caa cac ctg tcc tta ctg tgt gaa aaa tat agc act gta gtc
998Leu Thr Gln His Leu Ser Leu Leu Cys Glu Lys Tyr Ser Thr Val Val 175
180 185aga gat gag gta ggt gga aaa gta
cct tat ata gaa cag cat cag ttc 1046Arg Asp Glu Val Gly Gly Lys Val
Pro Tyr Ile Glu Gln His Gln Phe190 195
200 205aaa ctg tgc att atg agg agg agc aaa gga aga gca
gag aaa tct t 1092Lys Leu Cys Ile Met Arg Arg Ser Lys Gly Arg Ala
Glu Lys Ser 210 215
220aagacggtgg ccaaattaaa gtgctggcct tcagatgtct gtgatttctg caactgagga
1152cctaattatg cctgtctgca aactaataat gtaaaaggta ataattaaag tatcatattt
1212tcatgtggga aaaaaaaaaa aaaaaaaaaa aaaa
1246291111DNAH. sapiensCDS(297)...(957)K+Hnov44, splice 2 29aaaaaccatg
acttgtggca ccagaagaga gccggggact tcaatccaag aaagcagaga 60agataccaaa
gaaggaccga gaagggcaaa gcaaagaaga ctgtaccatg tcctaagctg 120aggcaggcgg
caggcgtggt gcacaagaag tctgagtgtg aggggctctt ttctctccac 180tgccaatgac
agcctttcct gcctcaggga agaagagaga gacagactac agtgatggag 240acccactaga
tgtgcacaag aggctgccat ccagtgctgg agaggaccga gccgtg atg 299Met1ctg ggg
ttt gcc atg atg ggc ttc tca gtc cta atg ttc ttc ttg ctc 347Leu Gly
Phe Ala Met Met Gly Phe Ser Val Leu Met Phe Phe Leu Leu 5
10 15gga aca acc att cta aag cct ttt atg
ctc agc att cag aga gaa gaa 395Gly Thr Thr Ile Leu Lys Pro Phe Met
Leu Ser Ile Gln Arg Glu Glu 20 25
30tcg acc tgc act gcc atc cac aca gat atc atg gac gac tgg ctg gac
443Ser Thr Cys Thr Ala Ile His Thr Asp Ile Met Asp Asp Trp Leu Asp 35
40 45tgt gcc ttc acc tgt ggt gtg cac tgc
cac ggt cag ggg aag tac ccg 491Cys Ala Phe Thr Cys Gly Val His Cys
His Gly Gln Gly Lys Tyr Pro50 55 60
65tgt ctt cag gtg ttt gtg aac ctc agc cat cca ggt cag aaa
gct ctc 539Cys Leu Gln Val Phe Val Asn Leu Ser His Pro Gly Gln Lys
Ala Leu 70 75 80cta cat
tat aat gaa gag gct gtc cag ata aat ccc aag tgc ttt tac 587Leu His
Tyr Asn Glu Glu Ala Val Gln Ile Asn Pro Lys Cys Phe Tyr 85
90 95aca cct aag tgc cac caa gat aga aat
gat ttg ctc aac agt gct ctg 635Thr Pro Lys Cys His Gln Asp Arg Asn
Asp Leu Leu Asn Ser Ala Leu 100 105
110gac ata aaa gaa ttc ttc gat cac aaa aat gga act ccc ttt tca tgc
683Asp Ile Lys Glu Phe Phe Asp His Lys Asn Gly Thr Pro Phe Ser Cys 115
120 125ttc tac agt cca gcc agc caa tct
gaa gat gtc att ctt ata aaa aag 731Phe Tyr Ser Pro Ala Ser Gln Ser
Glu Asp Val Ile Leu Ile Lys Lys130 135
140 145tat gac caa atg gct atc ttc cac tgt tta ttt tgg
cct tca ctg act 779Tyr Asp Gln Met Ala Ile Phe His Cys Leu Phe Trp
Pro Ser Leu Thr 150 155
160ctg cta ggt ggt gcc ctg att gtt ggc atg gtg aga tta aca caa cac
827Leu Leu Gly Gly Ala Leu Ile Val Gly Met Val Arg Leu Thr Gln His
165 170 175ctg tcc tta ctg tgt gaa
aaa tat agc act gta gtc aga gat gag gta 875Leu Ser Leu Leu Cys Glu
Lys Tyr Ser Thr Val Val Arg Asp Glu Val 180 185
190ggt gga aaa gta cct tat ata gaa cag cat cag ttc aaa ctg
tgc att 923Gly Gly Lys Val Pro Tyr Ile Glu Gln His Gln Phe Lys Leu
Cys Ile 195 200 205atg agg agg agc aaa
gga aga gca gag aaa tct t aagacggtgg 967Met Arg Arg Ser Lys
Gly Arg Ala Glu Lys Ser210 215
220ccaaattaaa gtgctggcct tcagatgtct gtgatttctg caactgagga cctaattatg
1027cctgtctgca aactaataat gtaaaaggta ataattaaag tatcatattt tcatgtggga
1087aaaaaaaaaa aaaaaaaaaa aaaa
111130220PRTH. sapiens 30Met Leu Gly Phe Ala Met Met Gly Phe Ser Val Leu
Met Phe Phe Leu1 5 10
15Leu Gly Thr Thr Ile Leu Lys Pro Phe Met Leu Ser Ile Gln Arg Glu
20 25 30Glu Ser Thr Cys Thr Ala Ile
His Thr Asp Ile Met Asp Asp Trp Leu 35 40
45Asp Cys Ala Phe Thr Cys Gly Val His Cys His Gly Gln Gly Lys
Tyr 50 55 60Pro Cys Leu Gln Val Phe
Val Asn Leu Ser His Pro Gly Gln Lys Ala65 70
75 80Leu Leu His Tyr Asn Glu Glu Ala Val Gln Ile
Asn Pro Lys Cys Phe 85 90
95Tyr Thr Pro Lys Cys His Gln Asp Arg Asn Asp Leu Leu Asn Ser Ala
100 105 110Leu Asp Ile Lys Glu Phe
Phe Asp His Lys Asn Gly Thr Pro Phe Ser 115 120
125Cys Phe Tyr Ser Pro Ala Ser Gln Ser Glu Asp Val Ile Leu
Ile Lys 130 135 140Lys Tyr Asp Gln Met
Ala Ile Phe His Cys Leu Phe Trp Pro Ser Leu145 150
155 160Thr Leu Leu Gly Gly Ala Leu Ile Val Gly
Met Val Arg Leu Thr Gln 165 170
175His Leu Ser Leu Leu Cys Glu Lys Tyr Ser Thr Val Val Arg Asp Glu
180 185 190Val Gly Gly Lys Val
Pro Tyr Ile Glu Gln His Gln Phe Lys Leu Cys 195
200 205Ile Met Arg Arg Ser Lys Gly Arg Ala Glu Lys Ser
210 215 2203122DNAArtificial
SequencePrimer 31tatccacatc aatggacaaa gc
223220DNAArtificial SequencePrimer 32tgcataactg gctgggtgta
203322DNAArtificial
SequencePrimer 33tgacatcact ggatgaactt ga
223420DNAArtificial SequencePrimer 34tgcctgcaaa gtttgaacat
203522DNAArtificial
SequencePrimer 35tgacatcact ggatgaactt ga
223620DNAArtificial SequencePrimer 36tgcctgcaaa gtttgaacat
203720DNAArtificial
SequencePrimer 37acctggtggt atggaagcat
203819DNAArtificial SequencePrimer 38tttctcctgg cctctaccc
193919DNAArtificial
SequencePrimer 39tccctcttgg gtgaccttc
194020DNAArtificial SequencePrimer 40atctttgtca gccaccagct
204124DNAArtificial
SequencePrimer 41aggtgtgctg ccatctgctg ttcg
244224DNAArtificial SequencePrimer 42agcctatcct ctctgagagt
cagg 244321DNAArtificial
SequencePrimer 43aagcagagta ctcatgatgc c
214420DNAArtificial SequencePrimer 44tctggtagac agtacagtgg
204520DNAArtificial
SequencePrimer 45catttggctg gtccaagatg
204620DNAArtificial SequencePrimer 46agtcattggt agggaggtac
204720DNAArtificial
SequencePrimer 47catgcttcta cagtccagcc
204820DNAArtificial SequencePrimer 48ggtcctcagt tgcagaaatc
204945DNAArtificial
SequencePrimer 49tggtgggctg tggtgaccat gacaactgtg ggctatgggg acatg
455045DNAArtificial SequencePrimer 50tggtgggcag tggtcaccat
gaccactgtg ggctacgggg acatg 455145DNAArtificial
SequencePrimer 51tggtgggcag tcgtctccat gacaactgta ggctatggag acatg
455245DNAArtificial SequencePrimer 52tggtgggcag tggtaaccat
gacaacagtg ggttacggcg atatg 455345DNAArtificial
SequencePrimer 53tggtgggctg tggtcaccat gacgaccctg ggctatggag acatg
455445DNAArtificial SequencePrimer 54tggtgggggg tggtcacagt
caccaccatc ggctatgggg acaag 455545DNAArtificial
SequencePrimer 55tggtgggcag tggtcaccat gaccacggtt ggctatgggg acatg
455645DNAArtificial SequencePrimer 56tggtgggccg tggtcaccat
gacgaccctg ggctatggag acatg 455745DNAArtificial
SequencePrimer 57tggtgggctg tggtcaccat gacgacactg ggctacggag acatg
455845DNAArtificial SequencePrimer 58tggtgggctg tggtgaccat
gacaactgtg ggctatgggg acatg 455947DNAArtificial
SequencePrimer 59ttcctgttct ccattgagac cgaaacaacc attgggtatg gcttccg
476047DNAArtificial SequencePrimer 60tttttattct caatagagac
agaaaccacc attggttatg gctaccg 476147DNAArtificial
SequencePrimer 61ttcctcttct ccattgagac ccagacaacc ataggctatg gtttcag
476247DNAArtificial SequencePrimer 62ttcctgttct cggtggagac
gcagacgacc atcggctatg ggttccg 476347DNAArtificial
SequencePrimer 63ttcctcttct cccttgaatc ccaaaccacc attggctatg gcttccg
476447DNAArtificial SequencePrimer 64tttctctttt ccctggaatc
ccagacaacc attggctatg gagtccg 476547DNAArtificial
SequencePrimer 65ttccttttct ccattgaggt ccaagtgact attggctttg gggggcg
476647DNAArtificial SequencePrimer 66tttctcttct ccattgaagt
tcaagttacc attgggtttg gagggag 476750DNAArtificial
SequencePrimer 67gcgctctact tcaccttcag cagcctcacc agtgtgggct tcggcaacgt
506815PRTArtificial Sequenceconsensus sequences 68Trp Trp
Ala Val Val Ser Met Thr Thr Val Gly Tyr Gly Asp Met1 5
10 156915PRTArtificial SequencePrimer 69Trp
Trp Ala Val Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met1 5
10 157015PRTArtificial SequencePrimer
70Trp Trp Gly Val Val Thr Val Thr Thr Ile Gly Tyr Gly Asp Lys1
5 10 157115PRTArtificial
SequencePrimer 71Trp Trp Ala Val Val Thr Met Thr Thr Val Gly Tyr Gly Asp
Met1 5 10
157215PRTArtificial SequencePrimer 72Phe Leu Phe Ser Ile Glu Val Gln Val
Thr Ile Gly Phe Gly Gly1 5 10
157315PRTArtificial SequencePrimer 73Phe Leu Phe Ser Leu Glu Ser Gln
Thr Thr Ile Gly Tyr Gly Val1 5 10
157415PRTArtificial SequencePrimer 74Phe Leu Phe Ser Ile Glu Thr
Glu Thr Thr Ile Gly Tyr Gly Tyr1 5 10
157515PRTArtificial SequencePrimer 75Phe Leu Phe Ser Ile Glu
Thr Gln Thr Thr Ile Gly Tyr Gly Phe1 5 10
157615PRTArtificial SequencePrimer 76Phe Leu Phe Ser Val
Glu Thr Gln Thr Thr Ile Gly Tyr Gly Phe1 5
10 157715PRTArtificial SequencePrimer 77Phe Leu Phe Ser
Leu Glu Ser Gln Thr Thr Ile Gly Tyr Gly Phe1 5
10 157815PRTArtificial SequencePrimer 78Phe Leu Phe
Ser Ile Glu Thr Glu Thr Thr Ile Gly Tyr Gly Phe1 5
10 157916PRTArtificial SequencePrimer 79Ala Leu
Tyr Phe Thr Phe Ser Ser Leu Thr Ser Val Gly Phe Gly Asn1 5
10 15802571DNAH.
sapiensCDS(110)...(1051) 80gctgccgcgc ctgtagcact cccggaactg gaactaggtg
ccagacggtc cggaggcggg 60ggccacgtca gcggggccac ccagggctcg cggggtcccg
gtgggtgcc atg cgg agg 118Met Arg Arg1ggc gcg ctt ctg gcg ggc gcc ttg
gcc gcg tac gcc gcg tac ctg gtg 166Gly Ala Leu Leu Ala Gly Ala Leu
Ala Ala Tyr Ala Ala Tyr Leu Val 5 10
15ctg ggc gcg ctg ttg gtg gcg cgg ctg gag ggg ccg cac gaa gcc agg
214Leu Gly Ala Leu Leu Val Ala Arg Leu Glu Gly Pro His Glu Ala Arg20
25 30 35ctc cga gcc gag ctg
gag acg ctg cgg gcg cag ctg ctt cag cgc agc 262Leu Arg Ala Glu Leu
Glu Thr Leu Arg Ala Gln Leu Leu Gln Arg Ser 40
45 50ccg tgt gtg gct gcc ccc gcc ctg gac gcc ttc
gtg gag cga gtg ctg 310Pro Cys Val Ala Ala Pro Ala Leu Asp Ala Phe
Val Glu Arg Val Leu 55 60
65gcg gcc gga cgg ctg ggg cgg gtc gtg ctt gct aac gct tcg ggg tcc
358Ala Ala Gly Arg Leu Gly Arg Val Val Leu Ala Asn Ala Ser Gly Ser
70 75 80gcc aac gcc tcg gac ccc gcc tgg
gac ttc gcc tct gct ctc ttc ttc 406Ala Asn Ala Ser Asp Pro Ala Trp
Asp Phe Ala Ser Ala Leu Phe Phe 85 90
95gcc agc acg ctg atc acc acc gtg ggc tat ggg tac aca acg cca ctg
454Ala Ser Thr Leu Ile Thr Thr Val Gly Tyr Gly Tyr Thr Thr Pro Leu100
105 110 115act gat gcg ggc
aag gcc ttc tcc atc gcc ttt gcg ctc ctg ggc gtg 502Thr Asp Ala Gly
Lys Ala Phe Ser Ile Ala Phe Ala Leu Leu Gly Val 120
125 130ccg acc acc atg ctg ctg ctg acc gcc tca
gcc cag cgc ctg tca ctg 550Pro Thr Thr Met Leu Leu Leu Thr Ala Ser
Ala Gln Arg Leu Ser Leu 135 140
145ctg ctg act cac gtg ccc ctg tct tgg ctg agc atg cgt tgg ggc tgg
598Leu Leu Thr His Val Pro Leu Ser Trp Leu Ser Met Arg Trp Gly Trp
150 155 160gac ccc cgg cgg gcg gcc tgc
tgg cac ttg gtg gcc ctg ttg ggg gtc 646Asp Pro Arg Arg Ala Ala Cys
Trp His Leu Val Ala Leu Leu Gly Val 165 170
175gta gtg acc gtc tgc ttt ctg gtg ccg gct gtg atc ttt gcc cac ctc
694Val Val Thr Val Cys Phe Leu Val Pro Ala Val Ile Phe Ala His Leu180
185 190 195gag gag gcc tgg
agc ttc ttg gat gcc ttc tac ttc tgc ttt atc tct 742Glu Glu Ala Trp
Ser Phe Leu Asp Ala Phe Tyr Phe Cys Phe Ile Ser 200
205 210ctg tcc acc atc ggc ctg ggc gac tac gtg
ccc ggg gag gcc cct ggc 790Leu Ser Thr Ile Gly Leu Gly Asp Tyr Val
Pro Gly Glu Ala Pro Gly 215 220
225cag ccc tac cgg gcc ctc tac aag gtg ctg gtc aca gtc tac ctc ttc
838Gln Pro Tyr Arg Ala Leu Tyr Lys Val Leu Val Thr Val Tyr Leu Phe
230 235 240ctg ggc ctg gtg gcc atg gtg
ctg gtg ctg cag acc ttc cgc cac gtg 886Leu Gly Leu Val Ala Met Val
Leu Val Leu Gln Thr Phe Arg His Val 245 250
255tcc gac ctc cac ggc ctc acg gag ctc atc ctg ctg ccc cct ccg tgc
934Ser Asp Leu His Gly Leu Thr Glu Leu Ile Leu Leu Pro Pro Pro Cys260
265 270 275cct gcc agt ttc
aat gcg gat gag gac gat cgg gtg gac atc ctg ggc 982Pro Ala Ser Phe
Asn Ala Asp Glu Asp Asp Arg Val Asp Ile Leu Gly 280
285 290ccc cag ccg gag tcg cac cag caa ctc tct
gcc agc tcc cac acc gac 1030Pro Gln Pro Glu Ser His Gln Gln Leu Ser
Ala Ser Ser His Thr Asp 295 300
305tac gct tcc atc ccc agg tag ctggggcagc ctctgccagg cttgggtgtg
1081Tyr Ala Ser Ile Pro Arg * 310cctggcctgg gactgagggg tccaggcgac
cagagctggc tgtacaggaa tgtccacgag 1141cacagcaggt gatcttgagg ccttgccgtc
caccgtctct cctttgtttc ccagcatctg 1201gctgggatgt gaagggcagc actccctgtc
cccatgtccc gggctccact gggcaccaac 1261ataaccttgt tctctgtcct ttctctcatc
ctctttacac tgtgtctctc tggctctctg 1321gcattctcgc tgcctctgtc tttccctctt
gctgtctctg tttctcattc tctttcatgt 1381tccgtctgtg tctctcaatt aaccactcgt
caactgctga ttctactggg ctgtgggctc 1441agacctcatt tcaggcacca gattggtcgc
tacaccctgg acaagtgact gcccgtctct 1501gagccttgat ttcctcagct gccaaatggg
aagaatagaa gaatttgccc ctaaacccct 1561cctgtgtgct ggccctgtgc tagacagtgc
tggagacata gttgggggtg gagaactgcc 1621cttatggagc ttgcagtcca gtgaggtgga
cagacctgtc cccagacagt gatggcccaa 1681aatggtcagg actttaatgg aggaggtgag
gtgttgaaag cacaggcaga gtggtcaggg 1741ctgaagtcgg agaagcatag ggactaggcc
caatccagcc tggaaagtca gggaggactt 1801cctagaggaa gggacatcga actaagacct
gaactatgag aaataggcag gaagaagttg 1861tacctgactc atttttctca ggtgtctcca
gggagcagga cccatggagg gacccctggt 1921gtaggcctgg gcgatagact cttcctcagc
agcctggcag gcaggaaaca gacataggac 1981cccagcccag atctgaatgg catgggaggt
gctgccctta accatgacac cattgtaaga 2041gctgtccaca tttgtatgtt gtgccctgga
atcagcctgg ttgagctcaa atcccaactt 2101agccacgtct ggcctgtgtc cttgggcagt
cacactacct ctctgatttt gtttccttat 2161ctgtaaaatg gtgatcatca taatacaact
tcaaaaggat ttcaggctga gtgtggtggc 2221tcacgcctat acacccagca ctttggaagg
ctgaggaagg aggatcgctt gaggccagga 2281gtttgagact agcctaggca acacagtgag
gccttatctc aacaacaacc acaaaatcta 2341aaaattagct gggtgtggtg gtgcatgcct
gtgatcctgg ctacttcaga ggctgaggtg 2401gaaggatcac ttgaggccag gagtttgagg
ctgcagtgag ttatgatggc actgctgcac 2461tccagcctgc gggacagagt gagaccctgt
ctgaaagaaa gagagaaaga aagaaagaaa 2521gagagagaaa gaaagaaaga aagaaaggga
aagatggaag gaaggaagga 257181313PRTH. sapiens 81Met Arg Arg
Gly Ala Leu Leu Ala Gly Ala Leu Ala Ala Tyr Ala Ala1 5
10 15Tyr Leu Val Leu Gly Ala Leu Leu Val Ala
Arg Leu Glu Gly Pro His 20 25
30Glu Ala Arg Leu Arg Ala Glu Leu Glu Thr Leu Arg Ala Gln Leu Leu
35 40 45Gln Arg Ser Pro Cys Val Ala Ala
Pro Ala Leu Asp Ala Phe Val Glu 50 55
60Arg Val Leu Ala Ala Gly Arg Leu Gly Arg Val Val Leu Ala Asn Ala65
70 75 80Ser Gly Ser Ala Asn
Ala Ser Asp Pro Ala Trp Asp Phe Ala Ser Ala 85
90 95Leu Phe Phe Ala Ser Thr Leu Ile Thr Thr Val
Gly Tyr Gly Tyr Thr 100 105
110Thr Pro Leu Thr Asp Ala Gly Lys Ala Phe Ser Ile Ala Phe Ala Leu
115 120 125Leu Gly Val Pro Thr Thr Met
Leu Leu Leu Thr Ala Ser Ala Gln Arg 130 135
140Leu Ser Leu Leu Leu Thr His Val Pro Leu Ser Trp Leu Ser Met
Arg145 150 155 160Trp Gly
Trp Asp Pro Arg Arg Ala Ala Cys Trp His Leu Val Ala Leu
165 170 175Leu Gly Val Val Val Thr Val
Cys Phe Leu Val Pro Ala Val Ile Phe 180 185
190Ala His Leu Glu Glu Ala Trp Ser Phe Leu Asp Ala Phe Tyr
Phe Cys 195 200 205Phe Ile Ser Leu
Ser Thr Ile Gly Leu Gly Asp Tyr Val Pro Gly Glu 210
215 220Ala Pro Gly Gln Pro Tyr Arg Ala Leu Tyr Lys Val
Leu Val Thr Val225 230 235
240Tyr Leu Phe Leu Gly Leu Val Ala Met Val Leu Val Leu Gln Thr Phe
245 250 255Arg His Val Ser Asp
Leu His Gly Leu Thr Glu Leu Ile Leu Leu Pro 260
265 270Pro Pro Cys Pro Ala Ser Phe Asn Ala Asp Glu Asp
Asp Arg Val Asp 275 280 285Ile Leu
Gly Pro Gln Pro Glu Ser His Gln Gln Leu Ser Ala Ser Ser 290
295 300His Thr Asp Tyr Ala Ser Ile Pro Arg305
310823300DNAH. sapiensCDS(50)...(1285) 82aaatgcctgc ccgtgcagct
cggagcgcgc agcccgtctc tgaataaga atg gcg gca 58Met Ala Ala1cct gac ttg
ctg gat cct aaa tct gcc gct cag aac tcc aaa ccg agg 106Pro Asp Leu
Leu Asp Pro Lys Ser Ala Ala Gln Asn Ser Lys Pro Arg 5
10 15ctc tcg ttt tcc acg aaa ccc aca gtg ctt gct tcc
cgg gtg gag agt 154Leu Ser Phe Ser Thr Lys Pro Thr Val Leu Ala Ser
Arg Val Glu Ser20 25 30
35gac acg acc att aat gtt atg aaa tgg aag acg gtc tcc acg ata ttc
202Asp Thr Thr Ile Asn Val Met Lys Trp Lys Thr Val Ser Thr Ile Phe
40 45 50ctg gtg gtt gtc ctc tat
ctg atc atc gga gcc acc gtg ttc aaa gca 250Leu Val Val Val Leu Tyr
Leu Ile Ile Gly Ala Thr Val Phe Lys Ala 55 60
65ttg gag cag cct cat gag att tca cag agg acc acc att
gtg atc cag 298Leu Glu Gln Pro His Glu Ile Ser Gln Arg Thr Thr Ile
Val Ile Gln 70 75 80aag caa aca
ttc ata tcc caa cat tcc tgt gtc aat tcg acg gag ctg 346Lys Gln Thr
Phe Ile Ser Gln His Ser Cys Val Asn Ser Thr Glu Leu 85
90 95gat gaa ctc att cag caa ata gtg gca gca ata aat
gca ggg att ata 394Asp Glu Leu Ile Gln Gln Ile Val Ala Ala Ile Asn
Ala Gly Ile Ile100 105 110
115ccg tta gga aac acc tcc aat caa atc agt cac tgg gat ttg gga agt
442Pro Leu Gly Asn Thr Ser Asn Gln Ile Ser His Trp Asp Leu Gly Ser
120 125 130tcc ttc ttc ttt gct
ggc act gtt att aca acc ata gga ttt gga aac 490Ser Phe Phe Phe Ala
Gly Thr Val Ile Thr Thr Ile Gly Phe Gly Asn 135
140 145atc tca cca cgc aca gaa ggc ggc aaa ata ttc tgt
atc atc tat gcc 538Ile Ser Pro Arg Thr Glu Gly Gly Lys Ile Phe Cys
Ile Ile Tyr Ala 150 155 160tta ctg
gga att ccc ctc ttt ggt ttt ctc ttg gct gga gtt gga gat 586Leu Leu
Gly Ile Pro Leu Phe Gly Phe Leu Leu Ala Gly Val Gly Asp 165
170 175cag cta ggc acc ata ttt gga aaa gga att gcc
aaa gtg gaa gat acg 634Gln Leu Gly Thr Ile Phe Gly Lys Gly Ile Ala
Lys Val Glu Asp Thr180 185 190
195ttt att aag tgg aat gtt agt cag acc aag att cgc atc atc tca aca
682Phe Ile Lys Trp Asn Val Ser Gln Thr Lys Ile Arg Ile Ile Ser Thr
200 205 210atc ata ttt ata cta
ttt ggc tgt gta ctc ttt gtg gct ctg cct gcg 730Ile Ile Phe Ile Leu
Phe Gly Cys Val Leu Phe Val Ala Leu Pro Ala 215
220 225atc ata ttc aaa cac ata gaa ggc tgg agt gcc ctg
gac gcc att tat 778Ile Ile Phe Lys His Ile Glu Gly Trp Ser Ala Leu
Asp Ala Ile Tyr 230 235 240ttt gtg
gtt atc act cta aca act att gga ttt ggt gac tac gtt gca 826Phe Val
Val Ile Thr Leu Thr Thr Ile Gly Phe Gly Asp Tyr Val Ala 245
250 255ggt gga tcc gat att gaa tat ctg gac ttc tat
aag cct gtc gtg tgg 874Gly Gly Ser Asp Ile Glu Tyr Leu Asp Phe Tyr
Lys Pro Val Val Trp260 265 270
275ttc tgg atc ctt gta ggg ctt gct tac ttt gct gct gtc ctg agc atg
922Phe Trp Ile Leu Val Gly Leu Ala Tyr Phe Ala Ala Val Leu Ser Met
280 285 290att gga gat tgg ctc
cga gtg ata tct aaa aag aca aaa gaa gag gtg 970Ile Gly Asp Trp Leu
Arg Val Ile Ser Lys Lys Thr Lys Glu Glu Val 295
300 305gga gag ttc aga gca cac gct gct gag tgg aca gcc
aac gtc aca gcc 1018Gly Glu Phe Arg Ala His Ala Ala Glu Trp Thr Ala
Asn Val Thr Ala 310 315 320gaa ttc
aaa gaa acc agg agg cga ctg agt gtg gag att tat gac aag 1066Glu Phe
Lys Glu Thr Arg Arg Arg Leu Ser Val Glu Ile Tyr Asp Lys 325
330 335ttc cag cgg gcc acc tcc atc aag cgg aag ctc
tcg gca gaa ctg gct 1114Phe Gln Arg Ala Thr Ser Ile Lys Arg Lys Leu
Ser Ala Glu Leu Ala340 345 350
355gga aac cac aat cag gag ctg act cct tgt agg agg acc ctg tca gtg
1162Gly Asn His Asn Gln Glu Leu Thr Pro Cys Arg Arg Thr Leu Ser Val
360 365 370aac cac ctg acc agc
gag agg gat gtc ttg cct ccc tta ctg aag act 1210Asn His Leu Thr Ser
Glu Arg Asp Val Leu Pro Pro Leu Leu Lys Thr 375
380 385gag agt atc tat ctg aat ggt ttg acg cca cac tgt
gct ggt gaa gag 1258Glu Ser Ile Tyr Leu Asn Gly Leu Thr Pro His Cys
Ala Gly Glu Glu 390 395 400att gct
gtg att gag aac atc aaa tag ccctctcttt aaataacctt 1305Ile Ala
Val Ile Glu Asn Ile Lys * 405 410aggcatagcc
ataggtgagg acttctctat gctctttatg actgttgctg gtagcatttt 1365ttaaattgtg
catgagctca aagggggaac aaaatagata cacccatcat ggtcatctat 1425catcaagaga
atttggaatt ctgagccagc actttctttc tgatgatgct tgttgaacgg 1485tccactttct
ttgatgagtg gaatgacaag caatgtctga tgcctttttg tgcccagact 1545gttttcctct
ctctttccct aatgtgccat aaggcctcag aatgaatgag aattgtttct 1605ggtaacaatg
tagctttgag ggatcagttc ttaacttttc agggtctacc taactgagcc 1665tagatatgga
ccatttatgg atgacaacaa tttttttttt gtaaatgaca agaaattctt 1725atgcagcctt
ttacctaaga aattttctgt cagtgcctta tcttatgaag aaacagaacc 1785tctctagcta
atgtgtggtt tctccttccc tgcccccacc cctaggctca cctctgcagt 1845cttttacccc
agttctccca tttgaatacc ataccttgct ggaaacagtg tgtaaaatga 1905ctgaagtgat
gatgcccgaa gatgaaatag atgccaaatt agatggacat tgaagcaaca 1965ctcagcgttg
cctagcgtta aaggcactgc agagaaatga ggtgcagagg tggcccctct 2025gagtatttat
ttgactcagg taccagtggt acatatatac agtgtaatta tgaccaggct 2085ggtaaaattg
gctgctcgca aacaatcccc ttttttcctg gcagtatttg gaatttatca 2145tttattaata
actatacatt tttaaaggca gaagaagaaa atctatctat catctatcta 2205tctatctatc
tatctatcta tctatctatc tatctatcta tctatctaaa tgacctgaca 2265gaagaaaact
gttaaaaatg gatattattg gaggggattt aaaacagtgg gtgtgaatta 2325tcattctgat
ggaaagaaaa tagcaaaaca atgtgttaca agtatttgct aataaacagt 2385atactgccag
cttctaattg ctttttgatg tatgaaaggc ttatataatt ttcttttcgt 2445tgggtgactt
ttgccagatg agaggaggtg gcacagtggt gagtgcaggg cacagtccta 2505gccttctgtg
ggtatacttt tggagttgtg acttggctgt gagggcagaa gttgaagttg 2565ggatcactgt
gactttgcac atggaaaaat gcagattgca ggcataattc atctctgaca 2625ttagagaaaa
agctgttata gcacaattta aattttgaga gtttgctgtg tttttttttc 2685acataaaaga
ggctgattat tctttttagt ttaattttat atcctgtaat tctttggatg 2745gttccaagat
tcagaaaaaa ttcagtaaat gcaccccgta aattgctacc ctttccttta 2805ttttcatact
tagatctgct gtacattgta tatatatata atttttaaaa tgcagaaaga 2865aaataatttc
cctaaatata attgcaaact gatttctttt acttttttgt gtctgggggt 2925gggagctgta
tctgaataag tggcattcag attagggtct tgaaaaataa acccagaatc 2985tttaaaagaa
gcaaataaac taatagacgc ttattttcca aaatttaaat ttaagctaga 3045aatgtaaata
ttcaattaat ttgttaaaag tacttttata aagttaaaaa aaatccaacc 3105aaaattttag
aaagtcaggc tcttttagaa agaaagctac acccatttcc tcaaataact 3165gttccgaaaa
tttatatggt ggaatgcgcc atgtataaac tgtgaattgt attgacaaat 3225aaagtttgta
attaaagtca aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3285aaaaaaaaaa
aaaaa 330083411PRTH.
sapiens 83Met Ala Ala Pro Asp Leu Leu Asp Pro Lys Ser Ala Ala Gln Asn
Ser1 5 10 15Lys Pro Arg
Leu Ser Phe Ser Thr Lys Pro Thr Val Leu Ala Ser Arg 20
25 30Val Glu Ser Asp Thr Thr Ile Asn Val Met
Lys Trp Lys Thr Val Ser 35 40
45Thr Ile Phe Leu Val Val Val Leu Tyr Leu Ile Ile Gly Ala Thr Val 50
55 60Phe Lys Ala Leu Glu Gln Pro His Glu
Ile Ser Gln Arg Thr Thr Ile65 70 75
80Val Ile Gln Lys Gln Thr Phe Ile Ser Gln His Ser Cys Val
Asn Ser 85 90 95Thr Glu
Leu Asp Glu Leu Ile Gln Gln Ile Val Ala Ala Ile Asn Ala 100
105 110Gly Ile Ile Pro Leu Gly Asn Thr Ser
Asn Gln Ile Ser His Trp Asp 115 120
125Leu Gly Ser Ser Phe Phe Phe Ala Gly Thr Val Ile Thr Thr Ile Gly
130 135 140Phe Gly Asn Ile Ser Pro Arg
Thr Glu Gly Gly Lys Ile Phe Cys Ile145 150
155 160Ile Tyr Ala Leu Leu Gly Ile Pro Leu Phe Gly Phe
Leu Leu Ala Gly 165 170
175Val Gly Asp Gln Leu Gly Thr Ile Phe Gly Lys Gly Ile Ala Lys Val
180 185 190Glu Asp Thr Phe Ile Lys
Trp Asn Val Ser Gln Thr Lys Ile Arg Ile 195 200
205Ile Ser Thr Ile Ile Phe Ile Leu Phe Gly Cys Val Leu Phe
Val Ala 210 215 220Leu Pro Ala Ile Ile
Phe Lys His Ile Glu Gly Trp Ser Ala Leu Asp225 230
235 240Ala Ile Tyr Phe Val Val Ile Thr Leu Thr
Thr Ile Gly Phe Gly Asp 245 250
255Tyr Val Ala Gly Gly Ser Asp Ile Glu Tyr Leu Asp Phe Tyr Lys Pro
260 265 270Val Val Trp Phe Trp
Ile Leu Val Gly Leu Ala Tyr Phe Ala Ala Val 275
280 285Leu Ser Met Ile Gly Asp Trp Leu Arg Val Ile Ser
Lys Lys Thr Lys 290 295 300Glu Glu Val
Gly Glu Phe Arg Ala His Ala Ala Glu Trp Thr Ala Asn305
310 315 320Val Thr Ala Glu Phe Lys Glu
Thr Arg Arg Arg Leu Ser Val Glu Ile 325
330 335Tyr Asp Lys Phe Gln Arg Ala Thr Ser Ile Lys Arg
Lys Leu Ser Ala 340 345 350Glu
Leu Ala Gly Asn His Asn Gln Glu Leu Thr Pro Cys Arg Arg Thr 355
360 365Leu Ser Val Asn His Leu Thr Ser Glu
Arg Asp Val Leu Pro Pro Leu 370 375
380Leu Lys Thr Glu Ser Ile Tyr Leu Asn Gly Leu Thr Pro His Cys Ala385
390 395 400Gly Glu Glu Ile
Ala Val Ile Glu Asn Ile Lys 405
4108420DNAH. sapiens 84catagccata ggtgaggact
208520DNAH. sapiens 85gagaggaaaa cagtctgggc
208620DNAH. sapiens 86ggacatcgaa
ctaagacctg 208720DNAH.
sapiens 87tcccatgcca ttcagatctg
20
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