MOCS1 was first reported in relation to autosomal recessive molybdenum cofactor deficiency A (MOCODA, MIM:252150) in 1998 (Reiss et al., PMID: 9731530). MOCODA is characterized by refractory neonatal seizures, dysmorphic features, ocular lens dislocation, and a characteristic urinary profile indicative of an underlying biochemical dysfunction (PMID:33017596). The underlying mechanism is a failure to synthesize molybdenum cofactor, leading to loss of function of the enzymes sulfite oxidase, xanthine oxidase, and aldehyde oxidase (PMID:33017596).
Six variants (four missense, one frameshift, and one canonical splice-site) that have been reported in eight probands in four publications (PMIDs: 9731530, 9634514, 9921896, 29274890) are included in this curation. Co-segregation with disease was observed in a large consanguineous kindred (PMID:9634514). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The mechanism of pathogenicity is known to be biallelic loss of function. The MOCS1 gene encodes two functional enzymes, MOCS1A and MOCS1B, that participate in sequential steps of molybdenum cofactor synthesis (PMID:33017596). Variants affecting either enzyme individually or both in combination are sufficient to cause MOCODA.
This gene-disease association is also supported by in vitro functional assays and a mouse model (PMID: 12471057, 17236133, 33017596). Alternative splicing of the MOCS1 transcript leads to the generation of two functional enzymes, the monomeric MOCS1A and the hexameric MOCS1B. Both proteins are imported into the mitochondrial matrix, where they sequentially catalyze the first and second steps of molybdenum cofactor synthesis (PMID: 33017596). MOCS1-deficient mice recapitulate both the developmental and biochemical phenotypes observed in MOCODA patients (PMID:12471057). These phenotypes can be rescued by lentiviral transfection with a human MOCS1 expression construct (PMID:17236133).
In summary, MOCS1 is definitively associated with autosomal recessive molybdenum cofactor deficiency A. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on April 8th, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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