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-alpha (TNF). TNF activates opposing pathways leading to caspase-8-mediated apoptosis as well as nuclear factor kappa B (NF-kappa B)-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-kappa B subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients' fibroblasts exhibited increased apoptosis in response to TNF, impaired NF-kappa B activation, and defective expression of NF-kappa B-dependent antiapoptotic genes. Rela+/-mice have similarly impaired NF-kappa B 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.