| First Author | Badran YR | Year | 2017 |
| Journal | J Exp Med | Volume | 214 |
| Issue | 7 | Pages | 1937-1947 |
| PubMed ID | 28600438 | Mgi Jnum | J:244578 |
| Mgi Id | MGI:5913357 | Doi | 10.1084/jem.20160724 |
| Citation | Badran YR, et al. (2017) Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration. J Exp Med 214(7):1937-1947 |
| abstractText | 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 kappaB (NF-kappaB)-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-kappaB subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients' fibroblasts exhibited increased apoptosis in response to TNF, impaired NF-kappaB activation, and defective expression of NF-kappaB-dependent antiapoptotic genes. Rela+/- mice have similarly impaired NF-kappaB 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. |
