Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration

J Exp Med. 2017 Jul 3;214(7):1937-1947. doi: 10.1084/jem.20160724. Epub 2017 Jun 9.


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.

Publication types

  • Case Reports

MeSH terms

  • Animals
  • Base Sequence
  • Cells, Cultured
  • Chronic Disease
  • Colitis / chemically induced
  • Colitis / genetics
  • Dextran Sulfate
  • Exome / genetics
  • Female
  • Fibroblasts / metabolism
  • Gene Expression Profiling / methods
  • Genes, Dominant / genetics*
  • Haploinsufficiency*
  • Humans
  • Male
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Oral Ulcer / genetics*
  • Pedigree
  • Sequence Analysis, DNA / methods
  • Skin Ulcer / genetics*
  • Transcription Factor RelA / genetics*
  • Transcription Factor RelA / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • NF-kappa B
  • RELA protein, human
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Dextran Sulfate

Associated data

  • GENBANK/hg-19