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

Biosynthesis of the molybdenum cofactor (MoCo) can be divided into (1) the formation of a precursor and (2) the latter's subsequent conversion, by mol ybdopterin synthase, into the organic moiety of MoCo. These two steps are r eflected by the complementation groups A and B and the two formally disting uished types of MoCo deficiency that have an identical phenotype. Both type s of MoCo deficiency result in a pleiotropic loss of all molybdoenzyme acti vities and cause severe neurological damage. MOCS1 is defective in patients with group A deficiency and has been shown to encode two enzymes for early synthesis via a bicistronic transcript with two consecutive open reading f rames (ORFs). MOCS2 encodes the small and large subunits of molybdopterin s ynthase via a single transcript with two overlapping reading frames. This g ene was mapped to 5q and comprises seven exons. The coding sequence and all splice site-junction sequences were screened for mutations, in MoCo-defici ent patients in whom a previous search for MoCS1 mutations had been negativ e. In seven of the eight patients whom we investigated, we identified MoCS2 mutations that, by their nature, are most likely responsible for the defic iency Three different frameshift mutations were observed, with one of them found on 7 of 14 identified alleles. Furthermore, a start-codon mutation an d a missense mutation of a highly conserved amino acid residue were found. The locations of the mutations confirm the functional role of both ORFs. On e of the patients with identified MOCS2 mutations had been classified as ty pe B, in complementation studies. These findings support the hypothetical m echanism, for both forms of MoCo deficiency, that formerly had been establi shed by cell-culture experiments.