The Genetic and Molecular Dissection of an Early-Onset Familial Mucocutaneous Ulcerative Condition


NE Morgan1, E Dorris1, E Cummins5, F Adeeb4, C Taylor5, S Savic3, O Killeen6, A Fraser4, AG Wilson1


1. University College Dublin, Centre for Arthritis Research, Dublin 4, Ireland 2. University Hospital Kerry, Rheumatology, Tralee, Ireland 3. University of Leeds, Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, United Kingdom 4. University Hospital Limerick, Rheumatology, Limerick, Ireland 5. University College Dublin, School of Medicine, Dublin, Ireland 6. Our Lady's Children's Hospital Crumlin, Rheumatology, Dublin, Ireland


Bechet’s disease (BD) is a heterogeneous multifactorial auto-inflammatory condition characterised 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. Recent studies reported monogenic mucocutaneous ulcerative syndromes with similarities to BD in a number of un-related families caused by mutations in NF-κB pathway genes; RELA, a transcription factor of the NF-κB family, and TNFAIP3, a negative regulator of NF-κB activity and inflammatory cytokine production. The NF-κB pathway is a ‘master-regulator’ of immune and inflammatory signalling with the ability to control expression of genes associated with inflammation, apoptosis and proliferation.


Five multi-case Irish families have been identified with a BD-like illness, primarily involving childhood-onset chronic oral and genital ulcers, whereby the genetic and molecular basis is unknown.


Whole exome sequencing (WES) was applied to identify potential disease-causing mutations. Cell-based approaches using a range of experimental models will subsequently be used to elucidate the biological impact of the mutations.


In the largest family, WES revealed segregation of a mutation in RELA (p65) with the condition. The mutation involves a cytosine deletion causing a His487ThrfsTer7 frameshift, resulting in a truncated protein. Using PBMCs isolated from patient and non-affected donor blood, it was found that the mutant is expressed at similar levels to wild-type p65. Overexpression studies in Rela-/- mouse embryo fibroblast (MEF) cells have revealed that the expression of the mutant significantly decreases NF-κB activity compared to the wild-type. Preliminary findings in Rela -/- MEF cells suggest that the expression of the mutant protein affects cellular apoptotic signalling processes. Genotyping of this variant in the other families revealed the presence of the wild-type allele only, suggesting genetic heterogeneity. Current genetic analysis of the remaining families with this condition is expected to reveal novel mutations.


This work has identified a novel mutation associated with a rare familial mucocutaneous ulcerative condition. Our study will further inform on the genetic basis and biological mechanism of a BD-like illness. This may lead to better, personalised treatment for patients resulting in earlier disease control and reduced tissue damage.