Mutations in the molybdenum cofactor biosynthetic genesMOCS1, MOCS2, andGEPH

Abstract

Molybdenum cofactor deficiency in humans results in the loss of the activity of molybdoenzymes sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. The resultant severe phenotype, which includes progressive neurological damage leading in most cases to early childhood death, results primarily from the deficiency of sulfite oxidase. All forms of molybdenum cofactor deficiency are inherited as autosomal recessive traits. The cofactor is an unstable reduced pterin with a unique four-carbon side chain, synthesized by a complex pathway that requires the products of at least four different genes (MOCS1, MOCS2, MOCS3, and GEPH). Disease-causing mutations have been identified in three of these genes: MOCS1, MOCS2, and GEPH. MOCS1 and MOCS2 have a bicistronic architecture; i.e., each gene encodes two proteins in different open reading frames. The protein products, MOCS1A and B and MOCS2A and B, are expressed either from different mRNAs generated by alternative splicing or by independent translation of a bicistronic mRNA. The gephyrin protein, encoded by a third locus, is required during cofactor assembly for insertion of molybdenum. A total of 32 different disease-causing mutations, including several common to more than one family, have been identified in molybdenum cofactor-deficient patients and their relatives.

Gephyrin: a central GABAergic synapse organizer

“…107 DISEASE IMPLICATIONS OF GEPHYRIN Some neurological disorders have been linked to gephyrin dysfunctions (e.g., stiff-person syndrome (Moersch-Woltman), hyperekplexia, temporal lobe epilepsy, molybdenum cofactor deficiency, autism and schizophrenia). [108][109][110][111][112][113] These diseases may be partly attributed to defects in the glycinergic system, which can be easily understood given the role of gephyrin in GlyR clustering. Gephyrin levels are reduced in the brains of patients suffering from Alzheimer's disease, but its direct involvement in this disorder has not yet been fully explored.…”

Molybdenum Cofactor Deficiency: A New HPLC Method for Fast Quantification of S-Sulfocysteine in Urine and Serum

“…Type A deficiency affects twothirds of all patients and is caused by a mutation in the MOCS1 gene (Reiss and Johnson 2003). While type A patients lack the first precursor in the biosynthetic pathway of Moco, cyclic pyranopterin monophosphate (cPMP) , type B patients accumulate cPMP due to mutations in the MOCS2 gene, which encodes the molybdopterin synthase (Reiss et al 1999).…”

Characterization of MOCS1A, an Oxygen-sensitive Iron-Sulfur Protein Involved in Human Molybdenum Cofactor Biosynthesis

“…In humans, defects in molybdenum cofactor biosynthesis lead to the pleiotropic loss of the molybdoenzymes sulfite oxidase, aldehyde oxidase, and xanthine dehydrogenase (2,3). Affected patients usually die shortly after birth and show neurological abnormalities, such as attenuated growth of the brain, untreatable seizures, and dislocated ocular lenses (4).…”

“…1) proposed to be involved in iron-sulfur (FeS) cluster binding (14,15), one is located near the N terminus (consensus sequence CX 3 CX 2 C where X denotes any amino acid), and one is near the C terminus (consensus sequence CX 2 CX 13 C). Several mutations identified in molybdenum cofactor deficiency patients are located in these conserved cysteine motifs indicating their functional importance for protein activity (2,3). Based on sequence similarities to proteins such as biotin synthase, pyruvate formate-lyase-activating enzyme, and anaerobic ribonucleotide reductase-activating enzyme, MOCS1A has been classified as a member of the superfamily of S-adenosylmethionine (AdoMet)-dependent radical enzymes (16).…”