RELA Haploinsufficiency

RELA haploinsufficiency is an autosomal dominant autoinflammatory disease caused by mutations in the RELA gene , which encodes RelA, a subunit of NF-κB. The patients' fibroblasts exhibit increased apoptosis in response to TNF, impaired NF-κB activation and defective expression of NF-κB-dependent anti-apoptotic genes.

The nuclear factor-κB (NF-κB) family of transcription factors regulates numerous genes that control innate and adaptive immunity. The transcription factors consist of heterodimers or homodimers of 5 subunits: NF-κB1/p50, NF-κB2/p52, RELA/p65, c-REL and REL-B. Mutations in these subunits usually cause immunological disorders with different penetrance and expressivity. The phenotype is influenced by the location and biochemical nature of the causative variant as well as other genetic and environmental factors. Monogenic RELA haploinsufficiency leads to TNF-dependent mucocutaneous ulcerations and inflammatory bowel disease.

Clinically, these patients present with mucosal ulcers and gastrointestinal symptoms such as abdominal pain, vomiting and diarrhea, which may resemble inflammatory bowel disease. Fever and increased acute phase reactants are also detectable.

Oral and/or genital ulcers are the most common mucocutaneous manifestations described in patients with RELA haploinsufficiency (Badran YR et al. 2017).

The treatment of chronic mucocutaneous ulceration is challenging and only some patients respond selectively to tumor necrosis factor-α (TNF) inhibitors (Badran YR et al. 2017).

Rela+/- mice have similarly impaired NF-κB activation, develop skin ulcers after TNF exposure, and exhibit severe dextran sodium sulfate-induced colitis that is ameliorated by TNF inhibition. These results demonstrate that biallelic RELA expression is a major contributor to stromal cell protection from TNF-mediated cell death, thus delineating the mechanisms that determine the efficacy of TNF inhibition in this disease.

1. Badran YR et al. (2017) Human RELA haploinsufficiency results in autosomaldominant chronic mucocutaneous ulceration. J Exp Med 214:1937-1947
2. Comrie WA et al. (2018) RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias. J Allergy Clin Immunol 141:1507-1510.
3. Uhlig HH (2013) Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut 62:1795-805.