| Summary: | Hidradenitis suppurativa (HS) is a chronic inflammatory dermatosis that presents with painful nodules, abscesses and sinus tracts in apocrine gland-bearing regions. Disease pathogenesis is poorly understood and there is a consequent paucity of effective treatment options. HS has been associated with smoking and obesity and can be inherited in an autosomal dominant (AD) manner. Heterozygous mutations in the gamma-secretase genes NCSTN, PSEN1 and PSENEN have recently been reported in some Chinese multiplex kindreds with HS. The overall aim of this programme of research was to understand the genetic architecture of HS, the ultimate goal being to clarify the molecular mechanisms involved in disease pathogenesis. The principle objectives were four-fold: 1/ Explore the involvement of mutations in NCSTN, PSEN1 and PSENEN in British familial cases of HS. 2/ Functionally characterise any identified mutations. 3/ Determine the contribution of mutations in NCSTN, PSEN1 and PSENEN in the general disease population. 4/ Analyse the clinical phenotype of individuals harbouring gamma-secretase gene mutations. Heterozygous gamma-secretase gene mutations were detected in affected individuals from two of seven British multiplex kindreds demonstrating AD inheritance. Mutations were detected in NCSTN (c.1125+1 G>A) and PSENEN (c.66_67insG) which resulted in aberrant splicing (p.Glu333_Gln367del) and a frameshift (p.Phe23ValfsX98) respectively. Both mutant transcripts appeared unstable and subject to decay in primary human fibroblasts. A corresponding reduction in respective protein expression in mutant versus wild type fibroblasts implied that haploinsufficiency of the gamma-secretase components may underlie the development of HS in those cases. This apparent haploinsufficiency did not however affect gamma-secretase endopeptidase or carboxypeptidase activity in vitro. Forty eight individuals were sequentially recruited from a tertiary referral HS clinic and screened for variation in NCSTN, PSENEN and PSEN1. Three individuals harboured novel variants in NCSTN but no novel or rare (<1% population frequency) variation was detected in PSEN1 or PSENEN. All three NCSTN variants were of uncertain pathogenicity. Mutations in the gamma-secretase genes NCSTN, PSENEN and PSEN1 would therefore appear to underlie up to 7% of British cases of HS. Phenotypic analysis of individuals with likely pathogenic gamma-secretase mutations revealed early onset, severe, widespread and treatment resistant disease often associated with atypical flexural pigmentation and prominent cystic changes in atypical areas. Given that gamma-secretase gene mutations only appear to underlie a small proportion of HS cases it was hypothesised that there is further genetic heterogeneity underlying HS. Unexplained familial cases and unrelated but carefully phenotyped and sub-grouped individuals were therefore assessed using a combination of traditional and next generation gene mapping techniques. No pathogenic mutations in additional genes were identified. The identification of gamma-secretase gene mutations in HS informs disease pathogenesis, potentially implicates the gamma-secretase-Notch signalling axis in disease development, provides a platform for ongoing functional studies and will hopefully facilitate the identification of new therapeutic targets in this debilitating disease. Ongoing genetic and functional investigation is now required to confirm the presence of further genetic heterogeneity and to establish the relevance of gamma-secretase-Notch signalling in the wider patient cohort.
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