Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration.

The treatment of chronic mucocutaneous ulceration is challenging, and only some patients respond selectively to inhibitors of tumor necrosis factor-α (TNF). TNF activates opposing pathways leading to caspase-8-mediated apoptosis as well as nuclear factor κB (NF-κB)-dependent cell survival. We investigated the etiology of autosomal-dominant, mucocutaneous ulceration in a family whose proband was dependent on anti-TNF therapy for sustained remission. A heterozygous mutation in RELA, encoding the NF-κB subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients' fibroblasts exhibited increased apoptosis in response to TNF, impaired NF-κB activation, and defective expression of NF-κB-dependent antiapoptotic genes. Rela+/- mice have similarly impaired NF-κB activation, develop cutaneous ulceration from TNF exposure, and exhibit severe dextran sodium sulfate-induced colitis, ameliorated by TNF inhibition. These findings demonstrate an essential contribution of biallelic RELA expression in protecting stromal cells from TNF-mediated cell death, thus delineating the mechanisms driving the effectiveness of TNF inhibition in this disease. © 2017 Badran et al.

Citation

Yousef R Badran, Fatma Dedeoglu, Juan Manuel Leyva Castillo, Wayne Bainter, Toshiro K Ohsumi, Athos Bousvaros, Jeffrey D Goldsmith, Raif S Geha, Janet Chou. Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration. The Journal of experimental medicine. 2017 Jul 03;214(7):1937-1947

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PMID: 28600438

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