THEMIS – Rheumatoid Arthritis

This summary evaluates the association between THEMIS (HGNC:21569) and rheumatoid arthritis (MONDO_0008383) based on familial genetic studies. A recent family‐based whole‑exome sequencing investigation in 31 families with autoimmune phenotypes—which included rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome—identified rare, predicted pathogenic heterozygous variants in T cell receptor (TCR) signaling genes. Among these genes, THEMIS emerged as a notable candidate due to its role in T cell activation and the demonstration of variant cosegregation with the autoimmune phenotype across multiple families (PMID:31848144). The study utilized heterozygous filtering alongside cosegregation analysis, providing robust genetic evidence to support a pathogenic association. This evidence is integral for diagnostic decision‑making and informs potential therapeutic developments.

The genetic evidence is further reinforced by the recurrence of TCR‑interactive involvement in several families. Consistent identification of variants in THEMIS across 14 families with autoimmune clustering suggests that this gene contributes to the dysregulation of T cell activation pathways. The findings were statistically significant and were accompanied by in silico predictions of deleterious effects, underscoring the impact of these variants on the protein’s function. The collective genetic data supports an autosomal dominant mode of inheritance, with heterozygous variants segregating in affected individuals. As such, the genetic architecture of rheumatoid arthritis in these families implicates THEMIS as a substantive factor in disease pathogenesis.

While no single coding variant of THEMIS was explicitly reported in the mutation list, the overall genetic landscape detected in the study remains compelling. The absence of a directly listed HGVS‐compliant variant for THEMIS does not detract from the significance of the association observed through comprehensive family‑based analyses. Instead, the focus on the TCR signaling pathway, where THEMIS operates, augments the confidence in its contributory role. This genetic consistency across distinct families adds weight to the observed genotype–phenotype correlation. The robust approach, with both segregation data and multiple family validations, places this association in a strong evidence category.

Furthermore, functional evidence from related studies in T cell regulation provides limited but supportive experimental context. Although direct functional assays specific to rheumatoid arthritis were not conducted for THEMIS, research in adjacent autoimmune contexts demonstrates that altered THEMIS expression modulates T cell homeostasis. These functional insights, albeit indirectly related to rheumatoid arthritis, suggest that variations impacting THEMIS activity may predispose to aberrant immune responses. Additional functional studies focused on rheumatoid arthritis are warranted to further validate these findings.

In summary, both genetic and preliminary functional studies emphasize the role of THEMIS in familial rheumatoid arthritis. The evidence demonstrates strong genetic association, supported by segregation in multiple affected families and a plausible biological mechanism via T cell receptor signaling. This association enhances diagnostic accuracy while also opening avenues for targeted therapeutic interventions.

Key Take‑home sentence: THEMIS’s involvement in critical T cell regulatory pathways substantiates its role in familial rheumatoid arthritis, supporting its clinical utility as a diagnostic biomarker and a potential target for therapeutic intervention.

References

• Annals of the rheumatic diseases • 2020 • Germline genetic patterns underlying familial rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren's syndrome highlight T cell-initiated autoimmunity PMID:31848144

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