TNFSF12 – Common Variable Immunodeficiency

Rare variation in TNFSF12 (TWEAK) has been preliminarily implicated in common variable immunodeficiency (CVID) through functional and limited genetic observations. In a multi-gene NGS panel of 19 CVID-related genes in 103 patients, no TNFSF12 variants were classified as pathogenic or likely pathogenic, underscoring the rarity of deleterious alleles in TNFSF12 (PMID:33859323). To date, a single autosomal dominant c.433C>T (p.Arg145Cys) variant in exon 6 segregates with hypogammaglobulinemia and recurrent infections in one kindred, providing limited genetic evidence for TNFSF12 involvement in CVID (PMID:23493554).

Functional studies of the R145C substitution demonstrate high-molecular-weight aggregation of mutant TWEAK, enhanced binding to BAFF, and dominant inhibition of BAFF-mediated noncanonical NF-κB signaling by blocking p100 processing to p52. These effects result in impaired B-cell survival, proliferation, and T-cell–independent isotype switching, recapitulating key features of humoral immunodeficiency and supporting a dominant-negative mechanism in CVID pathogenesis (PMID:23493554).

References

• Scientific Reports • 2021 • The impact of rare and low-frequency genetic variants in common variable immunodeficiency (CVID). PMID:33859323
• Proceedings of the National Academy of Sciences of the United States of America • 2013 • Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. PMID:23493554

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