MOCOS was first reported in relation to autosomal recessive xanthinuria type II in 2001 (Ichida et al., PMID: 11302742). Xanthinuria type II is characterized by elevated xanthine/hypoxanthine in the urine and serum, and simultaneous low or undetectable levels of uric acid. This is due to an inability to synthesize sulfurated molybdenum-cofactor, the enzymatic product of the MOCOS enzyme, which is necessary for the activity of both xanthine oxidase and aldehyde oxidase. Xanthine oxidase is required for converting xanthine/hypoxanthine into uric acid. Many affected individuals remain asymptomatic, though ~40% develop urolithiasis, and ~5-10% experience non-specific stomach and/or muscle pain (PMID:25370766).
Eight variants (five missense, one nonsense, two frameshift) that have been reported in eight probands in five publications (PMID: 11302742, 14624414, 17368066, 29935280, 34356852) are included in this curation. This gene-disease relationship is further supported by segregation evidence from two large families with multiple affected siblings (PMID: 17368066, 34356852). The mechanism of pathogenicity is known to be loss-of-function. This gene-disease association is also supported by expression studies, in vitro functional assays, and an animal model (PMID: 33017596, 16127175, 35372998). The MOCOS gene is most highly expressed in the liver and small intestine, which are the major sites of xanthine oxidase activity. Complete knock-out of the homologous gene in mice fully recapitulates the phenotypes observed in human patients, while also inducing late embryonic/perinatal lethality, failure to thrive, and early mortality that has not been observed in humans.
In summary, MOCOS is definitively associated with autosomal recessive xanthinuria type II. 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 GCEP on 8/12/2022 (SOP Version 9).
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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