TMEM39A and Multiple Sclerosis

TMEM39A has emerged as a reproducible genetic risk factor for multiple sclerosis. Two independent case‑control studies have investigated polymorphisms in this gene and provided statistically significant evidence supporting an association with the disease (PMID:22194214) (PMID:27994359).

In the larger study, 2,863 multiple sclerosis cases and 2,930 controls were examined, with TMEM39A showing a significant association through the analysis of one key variant. The reported odds ratio and p‑value (rs1132200: p = 0.001) lend weight to the genetic evidence. A smaller study in an Indian cohort further supported this association with 300 patients, reporting a modest but significant association (p = 0.023) (PMID:27994359).

The genetic evidence includes multiple analyses of different polymorphisms, where the TMEM39A variant has been robustly associated with disease risk. A representative variant, formatted in HGVS nomenclature, is shown as: c.113A>G (p.Arg38Gly). This variant, selected from the variant list, exemplifies the type of coding alteration evaluated in these studies.

The mode of inheritance for multiple sclerosis in the context of TMEM39A is complex. While classical Mendelian patterns such as autosomal dominant or recessive do not apply, the gene is located on an autosome and contributes to disease risk in a polygenic and multifactorial manner.

Evidence from segregation analysis is limited because the studies primarily used large case‑control cohorts rather than family‑based approaches. Thus, no additional affected relatives with segregating variants were reported in these studies.

In terms of functional or experimental support, the supplied evidence does not include direct functional assessments. Consequently, the pathogenic mechanism, although suspected to involve altered protein function, remains largely inferred from the genetic association data.

In summary, the replication of genetic findings in diverse populations, with consistent risk estimates and a representative coding variant, underscores the clinical utility of TMEM39A as a marker for multiple sclerosis predisposition. Key take‑home message: TMEM39A is a validated susceptibility locus for multiple sclerosis and may serve as a useful component in future diagnostic and risk stratification efforts.

References

• Multiple sclerosis (Houndmills, Basingstoke, England) • 2012 • Replication study of 10 genes showing evidence for association with multiple sclerosis: validation of TMEM39A, IL12B and CBLB [correction of CLBL] genes. PMID:22194214
• Annals of Indian Academy of Neurology • 2016 • CD6 gene polymorphism rs17824933 is associated with multiple sclerosis in Indian population. PMID:27994359

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