TMEM187 – Systemic Lupus Erythematosus

TMEM187 has emerged as a candidate gene associated with systemic lupus erythematosus (SLE) based on two independent, large‐scale genetic studies spanning multiple ancestral groups. Detailed fine mapping of the Xq28 region, which includes several genes, has provided evidence that genetic variation in this locus is significantly associated with SLE risk (PMID:22904263). In one study, over 15,783 case‑control subjects were analyzed, and the robust association was replicated in diverse populations. Such large‐scale evaluation supports the clinical relevance of TMEM187 as a contributor to SLE susceptibility. The genetic findings lay the groundwork for improved diagnostic insights in this multifactorial autoimmune disorder.

The genetic evidence is further bolstered by a meta‑analysis on two Chinese Han populations, which identified TMEM187 as an independent contributor to SLE. In this investigation, the variant rs17422 reached genome‑wide significance (P = 1.47×10^-15, OR = 0.75) and was replicated across additional Asian cohorts (PMID:25149475). Although family‐based segregation data were not provided, the large sample sizes in these studies offer strong statistical support for the association. This multi‐cohort replication underscores the role of X‑linked loci in complex diseases such as SLE.

While the direct variant spectrum in the SLE cohorts remains incompletely characterized, data from related studies provide relevant insights. Among the curated variants for TMEM187, the missense change c.708G>T (p.Gln236His) is reported in a study of high functioning autism spectrum disorder (PMID:31323913). This variant, described using standardized HGVS nomenclature with three‑letter amino acid codes, exemplifies the type of coding changes that may impact protein functionality. Although identified in a different clinical context, its inclusion highlights the importance of detailed variant assessment in elucidating gene–disease relationships.

Given the genomic location of TMEM187 on the X chromosome, the mode of inheritance is anticipated to be X‑linked. This X‑linked context may help explain the differential effects observed across genders and suggests that risk alleles in TMEM187 could contribute uniquely to the pathogenesis of SLE. The absence of detailed familial segregation data limits the ability to quantify the number of affected relatives; however, the robust case–control findings indirectly support an impactful genetic contribution from this locus.

Functional assays specifically addressing the role of TMEM187 in SLE pathology are currently lacking. No direct experimental studies have yet established its mechanism of action in immune modulation or autoimmunity. The experimental evidence from the Xq28 region, however, indicates that genes in this area may interact with crucial immune regulatory pathways. The limited functional data underscore the need for future in vitro or in vivo experiments to elucidate how TMEM187 variants might perturb molecular processes relevant to SLE.

In summary, TMEM187 has been robustly linked to systemic lupus erythematosus through replicated large‐scale genetic studies. The gene–disease association is supported by strong statistical evidence from multi‑ancestral case–control and meta‑analysis studies, which justify a ClinGen categorization of “Strong” despite the current lack of direct functional validation. The curated missense variant c.708G>T (p.Gln236His) further exemplifies the variant spectrum within TMEM187 and reinforces its potential clinical utility. Key take‑home message: Robust genetic associations, even in the absence of extensive functional studies, provide a valuable foundation for diagnostic decision‑making and guide future research in systemic lupus erythematosus.

References

• Annals of the rheumatic diseases • 2013 • Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups PMID:22904263
• Human molecular genetics • 2015 • Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus PMID:25149475
• International journal of molecular sciences • 2019 • High Functioning Autism with Missense Mutations in Synaptotagmin‑Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes: SYTL4‑Protein Modeling, Protein‑Protein Interaction, Expression Profiling and MicroRNA Studies PMID:31323913

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