TRIM22 – Inflammatory Bowel Disease

Very-early-onset inflammatory bowel disease (VEO-IBD) presents with granulomatous colitis and severe perianal disease in infants and young children. TRIM22 encodes an interferon-induced E3 ubiquitin ligase critical for innate immune signaling. Autosomal recessive homozygous variants in TRIM22 have been implicated in VEO-IBD. Whole-exome sequencing of a consanguineous infant with granulomatous colitis and severe perianal disease identified a homozygous missense variant c.1324C>T (p.Arg442Cys). This variant was subsequently found homozygously in two additional unrelated patients (PMID:26836588). No affected relatives were reported, consistent with autosomal recessive inheritance.

Functional assays in patient-derived primary cells and cell culture demonstrated that p.Arg442Cys abrogates TRIM22-mediated regulation of NOD2-dependent activation of interferon-β and NF-κB signaling. Computational network analyses further correlated the TRIM22–NOD2 axis with pathways associated with VEO-IBD and adult-onset inflammatory bowel disease (Inflammatory Bowel Disease). These concordant in vitro and in silico data support a loss-of-function mechanism for TRIM22 in VEO-IBD.

Integration of genetic and functional evidence yields a ClinGen Moderate classification for the TRIM22–inflammatory bowel disease association, based on three homozygous probands, autosomal recessive segregation, and consistent mechanistic data. Further replication in larger cohorts and functional rescue studies will be needed to reach a definitive level of evidence. Key Take-home: Homozygous TRIM22 c.1324C>T (p.Arg442Cys) disrupts NOD2 signaling and causes autosomal recessive VEO-IBD, guiding genetic diagnosis and potential targeting of the TRIM22–NOD2 pathway.

References

• Gastroenterology • 2016 • Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease. PMID:26836588

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