HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q

Article Abstract:

Hereditary deficiency of 3-hydroxy-3-methylglutaryl (HMG) CoA lyase (HL) brings with it episodes of hypoketotic hypoglycemia and coma. It shows up frequently and is clinically severe in Saudi Arabia. In nine Saudi HL-deficient probands genetic diversity was found. Six were homozygous for the missense mutation R41Q. Two were homozygous for the frameshift mutation F305fs(-2). In 32 probands that were non-Saudi and HL-deficient, three R41Q alleles were found. There are four other point damaging mutations in codons 41 and 42, which are important for normal HL catalysis. They account for 21 of 82 mutant alleles in the group of HL-deficient probands.

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Nearby stop codons in exons of the nerofibromatosis type 1 gene are disparate splice effectors

Article Abstract:

Mutations that generate premature-termination codons (PTCs) may bring on exon-skipping by a number of mechanisms. Stop mutations disrupt gene functions in different ways. They give rise to truncated polypeptides because of the PTCs and often affect metabolism of corresponding mRNAs. In neurofibromin transcripts from different neurofibromatosis type 1 (NF1) patients have skipping of exons that have PTCs. Several stop mutations in some base pairs in exons 7 and 37 have been characterized. Creation/disruption of exon sequences related to splicing and changes in the secondary structure of mRNA may cause splicing events seen in the NF1 gene.

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The DMPK gene of severely affected myotonic dystrophy patients is hypermethylated proximal to the largely expanded CTG repeat

Article Abstract:

The DMPK gene of patients with myotonic dystrophy that is severe is hypermethylated close to the very expanded CTG repeat. The methylation pattern on the 5' side of the CTG repeat in the DMPK gene of patients who have myotonic dystrophy has been characterized using methylation-sensitive restriction enzymes as has the DMPK gene of normal people. For most of the patients the disease was congenital. It appears that there is protein-DNA contact in normal genes at an Sp1 consensus binding site above the CTG repeat. Where the cells have a hypermethylated DMPK gene there is apparently a significant reduction of the interaction.

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