Human molybdopterin syntase gene: identification of a bicistronic transcript with overlapping reading frames

Article Abstract:

Certain homologies have been taken advantage of to isolate a cDNA for heterodimeric molybdopterin (MPT)-synthase. The enzyme is required for conversion of an unstable precursor into molybdopterin, the organic moiety of a unique cofactor called molybdenum cofactor (MoCo). This universal cofactor is required for activity of all human molybdoenzymes. In some human tissues only one size of mRNA that matches the bicistronic transcript was found. Mutagenesis and in vitro translation experiments showed that each open reading frame (ORF) is translated independently, resulting in synthesis of a 10-kDa protein and a 21-kDa protein for the small and large subunits. The work also showed that the 3'- proximal ORF of the bicistronic transcript is translated by leaky scanning.

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Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B

Article Abstract:

Biosynthesis of the molybdenum cofactor (MoCo) can be divided into formation of a precursor and the later conversion of that precursor by moldopterin synthase into the organic moiety of MoCo. Two kinds of MoCo deficiency bring a pleiotropic loss of all molybdoenzyme activity and great neurological damage. In a group of MoCo-deficient patients in whom a previous search for MOCS1 mutations had been negative coding sequence and all splice site-function sequences were screened for mutations. In 7/8 of the patients MOCS2 mutations were found. The locations of the mutations confirm the functional role of two consecutive open reading frames (ORFs). Findings support the proposed mechanism for both forms of MoCo deficiency already established in cell-culture experiments.

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Long-term rescue of a lethal inherited disease by adeno-associated virus-mediated gene transfer in a mouse model of molybdenum-cofactor deficiency

Article Abstract:

A recombinant-expression cassette is constructed for the gene MOCS1 which via alternative splicing, facilitates the expression of the proteins MOCS1A and MOCS1B, both of which are necessary for the formation of a first intermediate, cyclic pyranopterin monophosphate within the biosynthetic pathway leading to active molybdenum cofactor (MoCo). A recombinant adeno-associated virus vector is used to express the artificial MOCS1 minigene to cure the lethal MOCS1-deficient phenotype.

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