A Novel RELA Truncating Mutation in a Familial Behçet’s Disease–like Mucocutaneous Ulcerative Condition

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.

Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: a retrospective cohort study

“…RelA is also known as p65 and is critically involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) heterodimer formation and consequent activation of NF-κB-mediated proinflammatory signalling. RelA haploinsufficiency has been reported as a cause of chronic mucocutaneous ulceration and familial Behçet’s disease (46, 47). Badran et al reported a family of four affected family members with mucocutaneous ulceration harbouring a mutation in the canonical donor splice site of exon 6 (NM_021975:c.559+1G>A), likely leading to a premature stop codon and haploinsufficiency (46).…”

“…Although RELA has already been reported as an IEI gene in a previous IUIS classification (48), it was not yet listed in the IEI in silico gene panel of our Department of Human Genetics (25), because evidence was considered insufficient at the time. Based on these arguments, this DNV has only now been classified as pathogenic, which could carry implications for therapy with anti-tumour necrosis factor alpha (TNFα) inhibitors (47).…”

Skin manifestations of inborn errors of NF-κB

“…Haploinsufficiency for RELA has been reported to present with mouth and genital ulcers, recurrent fever, colitis and mucocutaneous ulceration ( 105 , 106 ). Ulceration was attributed to heightened sensitivity to the apoptotic effects of TNF.…”

Paediatric Behçet’s Disease: A Comprehensive Review with an Emphasis on Monogenic Mimics

“…Using WES, Adeeb et al recently identified five familial cases of a novel RELA -truncating mutation that resulted in BD-like mucocutaneous ulcerations and neuromyelitis optica in three generations of an Irish family [ 108 ]. Data from this case series indicated that loss-of-function mutations in RELA impaired NF-κB signalling and increased apoptosis, causing the BD-like phenotype [ 108 ] ( Figure 1 C).…”