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

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dc.contributor.author Adeeb, Fahd
dc.contributor.author Dorris, Emma R.
dc.contributor.author Morgan, Niamh E.
dc.contributor.author Lawless, Dylan
dc.contributor.author Maqsood, Aqeel
dc.contributor.author Ng, Wan Lin
dc.contributor.author Killeen, Orla
dc.contributor.author Cummins, Eoin P.
dc.contributor.author Taylor, Cormac T.
dc.contributor.author Savic, Sinisa
dc.contributor.author Wilson, Anthony G.
dc.contributor.author Fraser, Alexander D.
dc.date.accessioned 2020-10-15T08:59:38Z
dc.date.issued 2020
dc.identifier.uri http://hdl.handle.net/10344/9335
dc.description peer-reviewed en_US
dc.description.abstract 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. en_US
dc.language.iso eng en_US
dc.publisher Wiley and Sons Ltd en_US
dc.relation 779295 en_US
dc.relation.ispartofseries Arthritis and Rheumatism; 73 (3), pp. 490-497
dc.relation.uri https://doi.org/10.1002/art.41531
dc.rights This is the peer reviewed author version of the following article: A novel RELA truncating mutation in familial Behçet’s Disease-like mucocutaneous ulcerative condition, which has been published in final form at https://doi.org/10.1002/art.41531 . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. http://olabout.wiley.com/WileyCDA/Section/id-828039.html#terms en_US
dc.subject Behçet’s Disease (BD) en_US
dc.subject mutation en_US
dc.subject autoinflammation en_US
dc.title A novel RELA truncating mutation in familial Behçet’s Disease-like mucocutaneous ulcerative condition en_US
dc.type info:eu-repo/semantics/article en_US
dc.type.supercollection all_ul_research en_US
dc.type.supercollection ul_published_reviewed en_US
dc.identifier.doi 10.1002/art.41531
dc.contributor.sponsor ERC en_US
dc.contributor.sponsor SFI en_US
dc.contributor.sponsor National Children’s Research Centre en_US
dc.relation.projectid C/18/6 en_US
dc.relation.projectid 15/CDA/3490 en_US
dc.relation.projectid 779295 en_US
dc.date.embargoEndDate 2021-09-23
dc.embargo.terms 2021-09-23 en_US
dc.rights.accessrights info:eu-repo/semantics/openAccess en_US


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