MOCS2 – Sulfite Oxidase Deficiency due to Molybdenum Cofactor Deficiency Type B

MOCS2 encodes the small and large subunits of molybdopterin synthase and is essential for molybdenum cofactor (MoCo) biosynthesis. Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B is an autosomal recessive metabolic disorder characterized by neonatal-onset intractable seizures, spasticity, hypouricemia and craniofacial dysmorphism (MOCS2; sulfite oxidase deficiency due to molybdenum cofactor deficiency type B). Initial reports in 1999 documented MOCS2 defects in seven of eight patients with frameshift, start‐codon and missense mutations, establishing the gene–disease link (PMID:10053004).

Subsequent case series have expanded the variant spectrum. Exome sequencing identified a novel in-frame indel c.472_477del in a patient presenting with neonatal seizures and hypouricemia (PMID:33066491). Most recently, a homozygous in-frame indel c.471_477delTTTAAAAinsG was described in an Ohtahara‐syndrome case, bringing the total to 37 affected individuals worldwide (PMID:36980992).

Segregation analyses confirm autosomal recessive inheritance: parents of affected probands are obligate carriers and variants co‐segregate with disease. A distant maternal founder effect was suggested by identical mitochondrial haplotypes in one kindred, supporting a shared ancestral allele (PMID:36980992).

Functional assays demonstrate that pathogenic MOCS2 variants abolish molybdopterin synthase activity. In vitro expression of a stop‐loss MOCS2B mutant abolished binding to both precursor Z and the MOCS2A subunit (PMID:16021469). Structural modeling of in-frame deletions predicts disruption of subunit interfaces and active‐site geometry (PMID:33066491).

A Mocs2 knock‐out mouse recapitulates the human phenotype, exhibiting neonatal lethality, absence of MoCo‐dependent enzyme activities, hypouricemia, elevated sulfite, neurodegeneration and renal calculi (PMID:27138983). This concordance across species underscores haploinsufficiency as the pathogenic mechanism.

Integration of robust genetic and experimental data supports a Definitive gene–disease association. Molecular diagnosis of MOCS2 variants enables early confirmation, guides reproductive planning via PGT-M and informs future therapeutic development. Key take‐home: Comprehensive MOCS2 variant detection is critical for diagnosis, family counseling and potential enzyme‐replacement strategies.

References

• American journal of human genetics • 1999 • Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B. PMID:10053004
• 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
• Diagnostics (Basel, Switzerland) • 2020 • Proteins Structure Models in the Evaluation of Novel Variant (C.472_477del) in the MOCS2 Gene. PMID:33066491
• Human genetics • 2016 • Mouse model for molybdenum cofactor deficiency type B recapitulates the phenotype observed in molybdenum cofactor deficient patients. PMID:27138983
• Genes • 2023 • Live Birth of a Healthy Child in a Couple with Identical mtDNA Carrying a Pathogenic c.471_477delTTTAAAAinsG Variant in the MOCS2 Gene. PMID:36980992

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