A novel RELA truncating mutation in familial Behçet’s Disease-like mucocutaneous ulcerative condition

Objectives Monogenic Behçet’s Disease (BD)‐like conditions are increasingly recognised and to date predominantly involve loss‐of‐function variants in TNFAIP3. The objective of this study was to identify genetic and pathobiological mechanisms associated with a BD‐like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in a three‐generation Irish family (n=5 cases; n=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 RELA expression in peripheral blood mononuclear cells was compared by western blot. Human epithelial and RelA‐/‐ mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to TNF. NF‐κB signalling, transcriptional activation, apoptosis and cytokine production was 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 members. This mutation results in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting two 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 fibroblast (MEF) cells expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing RELAWT, however there was no difference in RELA nuclear translocation. In RelA‐/‐ MEF expression of RELAp.His487ThrfsTer7 resulted in 1.98‐fold higher ratio of cleaved caspase‐3/caspase‐3 induced by TNF (p=0.036) compared to RELAWT. Conclusions Our data support RELA loss‐of‐function mutations as causing BD‐like autoinflammation and NMO via impaired NF‐κB signalling and increased apoptosis.