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Abstract Number: 918

A Novel Familial RELA Truncation Is Associated with Behçet’s-like Mucocutaneous Ulceration Syndrome

Emma Dorris1, Fahd Adeeb2, Eoin Cummins3, Sinisa Savic4, Sandy Fraser5 and Anthony G. Wilson6, 1UCD Conway Institute,, UCD Centre for Arthritis Research, Dublin 4, Ireland, 2Department of Rheumatology, University of Limerick, LIMERICK, Ireland, 3School of Medicine, Dublin 4, Ireland, 4Leeds Institute of Rheumatic and Musculoskeletal Medicine, The University of Leeds, Leeds, United Kingdom, 5Rheumatology, Croom Orthopedic Hospital, Ireland, Limerick, Ireland, 6UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin, Ireland

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Autoinflammation, Behcet's syndrome, family studies and genetics

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Session Information

Date: Sunday, October 21, 2018

Session Title: 3S103 ACR Abstract: Genetics, Genomics & Proteomics: Precision Medicine (916–921)

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Bechet’s disease (BD) is a heterogeneous multifactorial auto-inflammatory condition characterized by recurrent episodes of oral and genital ulceration, uveitis and skin lesions, with less frequent involvement of the gastrointestinal tract, large blood vessels and central nervous system.  The NF-κB pathway is a ‘master-regulator’ of immune and inflammatory signaling, with the ability to control the expression of key inflammatory genes and genes associated with apoptosis and proliferation.

Methods: This study involved a 3-generation family with Behçet’s-like mucocutaneous ulceration syndrome; primarily involving childhood-onset chronic oral and genital ulcers (figure 1). ISGBD criteria were used to diagnose Behçet’s Disease (BD). DNA was isolated from PBMCs from affected patients and non-affected familial controls. DNA sequencing identified a cysteine deletion at position 1459 in RELA which segregated with the condition. Immunoblot analysis of RELA confirmed protein truncation. PBMCs were stimulated with TNF and NFkB phosphorylation was measured relative to unstimulated controls.

Results: A heterozygous cysteine deletion at position 1459 in RELA was detected in affected individuals. This mutation is coding, inducing a frameshift His487ThrfsTer7, predicted to produce a truncated protein of 492 amino acids which would result in a ~6kDa smaller protein. This truncation was confirmed by immunoblot, with the affected individuals producing two bands: the wild-type and truncated protein whereas unaffected controls produced only the wildtype protein. Preliminary data indicates RelAHis487ThrfsTer7 heterozygotes have different kinetics in response to TNF, as measured by phosphorylation of RELA.

 

Conclusion: This study gives novel information on both the genetic basis and biological mechanisms of BD in individual families. Familial mutations that induce haploinsufficiency of RELA have recently been associated with BD. However, the His487ThrfsTer7 results in protein truncation rather than haploinsufficiency. Crucially, the His487ThrfsTer7 mutation interrupts the two C-terminal RELA transactivating domains.  Our study supports several recently published studies that loss-of-function mutations in the NF-κB pathway are linked with the development of familial early-onset BD-like syndromes.  Understanding both the genetic basis and biological mechanisms facilitates personalized medicines approaches that target the primary disease mediators, which result in earlier disease control and reduced tissue damage.

 


Disclosure: E. Dorris, None; F. Adeeb, None; E. Cummins, None; S. Savic, None; S. Fraser, None; A. G. Wilson, None.

To cite this abstract in AMA style:

Dorris E, Adeeb F, Cummins E, Savic S, Fraser S, Wilson AG. A Novel Familial RELA Truncation Is Associated with Behçet’s-like Mucocutaneous Ulceration Syndrome [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/a-novel-familial-rela-truncation-is-associated-with-behcets-like-mucocutaneous-ulceration-syndrome/. Accessed January 17, 2021.
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