A Novel RELA Truncating Mutation in a Familial Behçet's Disease-like Mucocutaneous Ulcerative Condition

Arthritis Rheumatol. 2021 Mar;73(3):490-497. doi: 10.1002/art.41531. Epub 2021 Feb 15.

Abstract

Objective: Monogenic Behçet's disease (BD)-like conditions are increasingly recognized and to date have been found to predominantly involve loss-of-function variants in TNFAIP3. This study was undertaken to identify genetic and pathobiologic mechanisms associated with a BD-like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in 3 generations of an Irish family (n = 5 cases and 5 familial controls).

Methods: Whole-exome sequencing was used to identify potential pathogenic variants in affected family members and determine segregation between affected and unaffected individuals. Relative v-rel reticuloendotheliosis viral oncogene homolog A (RELA) expression in peripheral blood mononuclear cells was compared by Western blotting. Human epithelial and RelA-/- mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to tumor necrosis factor (TNF). NF-κB signaling, transcriptional activation, apoptosis, and cytokine production were compared between wild-type and truncated RELA in experimental systems and patient samples.

Results: A heterozygous cytosine deletion at position c.1459 in RELA was detected in affected family members. This mutation resulted in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting 2 transactivation domains. The truncated RELA protein lacks a full transactivation domain. The RELA protein variants were expressed at equal levels in peripheral mononuclear cells. RelA-/- mouse embryonic fibroblasts (MEFs) expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing wild-type RELA; however, there was no difference in RELA nuclear translocation. In RelA-/- MEFs, expression of RELAp.His487ThrfsTer7 resulted in a 1.98-fold higher ratio of cleaved caspase 3 to caspase 3 induced by TNF compared to wild-type RELA (P = 0.036).

Conclusion: Our data indicate that RELA loss-of-function mutations cause BD-like autoinflammation and NMO via impaired NF-κB signaling and increased apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Apoptosis / genetics*
  • Apoptosis / immunology
  • Behcet Syndrome / genetics*
  • Behcet Syndrome / immunology
  • Child
  • Cytokines / immunology*
  • Female
  • Fibroblasts
  • Frameshift Mutation
  • Humans
  • Ireland
  • Loss of Function Mutation
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • NF-kappa B / immunology*
  • Neuromyelitis Optica / genetics*
  • Neuromyelitis Optica / immunology
  • Oral Ulcer / genetics
  • Oral Ulcer / immunology
  • Pedigree
  • Skin Ulcer / genetics
  • Skin Ulcer / immunology
  • Transcription Factor RelA / genetics*
  • Transcription Factor RelA / immunology
  • White People
  • Young Adult

Substances

  • Cytokines
  • NF-kappa B
  • RELA protein, human
  • Transcription Factor RelA