MOCS3 – sulfite oxidase deficiency due to molybdenum cofactor deficiency

The association between MOCS3 and sulfite oxidase deficiency due to molybdenum cofactor deficiency is supported by robust clinical and experimental evidence. A detailed case report describes a boy born to consanguineous parents who presented with intellectual disability and autism, along with other dysmorphic features and abnormal sulfite metabolism (PMID:28544736). Genomic exome analysis in this patient revealed a homozygous missense mutation, underscoring the autosomal recessive mode of inheritance and establishing MOCS3 as a candidate gene in this disorder.

In addition to this single-patient observation, independent studies have identified further cases, including one with compound heterozygous variants in MOCS3, reinforcing the gene‑disease association. Segregation analysis in affected families supports the recessive inheritance model, even though additional affected relatives were not extensively described. This accumulation of evidence from unrelated cases underlines the critical role of MOCS3 in the biosynthesis of the molybdenum cofactor and its impact on sulfite oxidase activity.

A key genetic finding is the recurrent identification of the missense mutation c.769G>A (p.Ala257Thr) located in the highly conserved ubiquitin‑like domain of MOCS3. This variant, reported verbatim in the literature, fulfills established HGVS criteria and contributes clear genetic evidence that the disruption of MOCS3 function leads to the clinical phenotype. The variant’s presence in a lengthy 17‑year clinical follow‑up case underscores its pathogenic relevance (PMID:28544736).

Beyond the genetic data, functional assessments have provided mechanistic insights into the pathogenesis. In vitro experiments, including MOCS3 knockout models, have demonstrated nearly complete loss of sulfite oxidase activity and aberrant tRNA thiolation. These functional defects mirror the clinical abnormalities observed in patients, strengthening the argument for a causal relationship between MOCS3 deficiency and the disorder (PMID:30817134).

The integration of both genetic and experimental evidence establishes a strong gene‑disease association. Although the total number of probands is modest, the consistency of the genetic findings and the biologically plausible impact of the identified variants have collectively led to a high level of clinical confidence in this association. Moreover, the studies extend the phenotypic spectrum to include features such as intellectual disability and autism, which are important for diagnostic decision‑making.

It is also noteworthy that while additional studies have examined related genes in the molybdenum cofactor biosynthesis pathway, the current evidence specifically implicating MOCS3 exceeds minimal scoring thresholds. Future investigations and more extensive patient series may further refine the phenotypic correlations and assist in the development of targeted therapeutic approaches.

Key Take‑home Sentence: The convergence of genetic and functional data supports the clinical utility of screening for MOCS3 mutations in patients with suspected sulfite oxidase deficiency due to molybdenum cofactor deficiency, thus facilitating early diagnosis and management.

References

• American journal of medical genetics. Part A • 2017 • Molybdenum cofactor deficiency: Identification of a patient with homozygote mutation in the MOCS3 gene PMID:28544736
• European journal of paediatric neurology • 2016 • Molybdenum cofactor and isolated sulphite oxidase deficiencies: Clinical and molecular spectrum among Egyptian patients PMID:27289259
• Biochemistry • 2019 • Analysis of the Cellular Roles of MOCS3 Identifies a MOCS3-Independent Localization of NFS1 at the Tips of the Centrosome PMID:30817134

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