MOCS2 – Sulfite oxidase deficiency due to molybdenum cofactor deficiency

Molybdenum cofactor synthesis 2 (MOCS2; HGNC:7193) encodes the small and large subunits of molybdopterin synthase, the terminal enzyme in molybdenum cofactor (MoCo) biosynthesis. Pathogenic biallelic variants in MOCS2 cause MoCo deficiency type B, an autosomal recessive disorder characterized by combined loss of sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase activities. The resulting sulfite oxidase deficiency underlies the neurologic and systemic manifestations of MONDO:0020480.

Genetic evidence includes over 35 unrelated probands with homozygous or compound heterozygous MOCS2 variants such as c.265T>C (p.Ter89Gln) segregating with disease (PMID:31201073). Reports describe missense, nonsense, splice-site, and frameshift mutations across seven exons, with consanguineous and non-consanguineous pedigrees confirming autosomal recessive inheritance and co-segregation.

Functional studies demonstrate that MOCS2 mutations abolish molybdopterin synthase activity. In vitro characterization of novel MOCS2 variants reveals disrupted binding of precursor Z and subunit interactions, leading to loss of enzyme function (PMID:16021469). A Mocs2 knockout mouse model recapitulates the human biochemical and neurologic phenotype, showing undetectable MoCo-dependent enzyme activities, elevated sulfite and purine metabolites, neuronal apoptosis, and early postnatal lethality (PMID:27138983).

Clinically, MoCo deficiency type B presents in the neonatal period with intractable seizures (HP:0001250), feeding difficulties (HP:0011968), progressive encephalopathy, microcephaly (HP:0000252), spastic quadriplegia (HP:0002510), and diffuse cerebral atrophy (HP:0002059). Late-onset or mild phenotypes exhibit developmental regression (HP:0002376), intellectual disability (HP:0001249), and occasional ectopia lentis (HP:0001083) (PMID:30900395).

While cyclic pyranopterin monophosphate (cPMP) replacement is effective in MoCo deficiency type A, there is currently no approved therapy for type B. Early molecular diagnosis via newborn screening and prenatal testing enables accurate genetic counseling and family planning (PMID:20385644; PMID:12533804).

Given the robust genetic, segregation, and functional concordance, the MOCS2–MoCo deficiency type B association meets ClinGen definitive criteria. Molecular diagnosis informs prognosis and genetic counseling, highlighting the urgent need for targeted therapies in this otherwise lethal disorder.

References

• Pediatric neurology • 2019 • The Clinical and Molecular Characteristics of Molybdenum Cofactor Deficiency Due to MOCS2 Mutations. PMID:31201073
• Human genetics • 2005 • Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase. PMID:16021469
• Human genetics • 2016 • Mouse model for molybdenum cofactor deficiency type B recapitulates the phenotype observed in molybdenum cofactor deficient patients. PMID:27138983
• Molecular genetics & genomic medicine • 2019 • Mild phenotype in Molybdenum cofactor deficiency: A new patient and review of the literature. PMID:30900395
• Pediatrics • 2010 • Successful treatment of molybdenum cofactor deficiency type A with cPMP. PMID:20385644
• Prenatal diagnosis • 2003 • Prenatal diagnosis of molybdenum cofactor deficiency and isolated sulfite oxidase deficiency. PMID:12533804

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