775 A new phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN
Journal of Investigative Dermatology(2018)
摘要
Dowling-Degos disease (DDD) is a rare disorder featuring reticulate pigmentation and hair follicular involvement and resulting from mutations in KRT5, POFUT1 and POGLUT1. Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the hair follicle unit which can be caused by mutations in four genes (including PSENEN) encoding the -secretase complex. Both HS and DDD typically involve the flexural areas of the body. During the past 10 years, we encountered 4 patients who presented with clinical features consistent with both DDD and HS and aimed at identifying the genetic cause of coexisting DDD and HS. We initially excluded KRT5, POGLUT1 and POFUT1 mutations in all 4 patients. We then screened PSENEN for pathogenic mutations using Sanger sequencing since this gene was recently reported to be associated with the double phenotype displayed by our patients. We identified in all 4 affected individuals an hitherto unreported heterozygous c.168T>G, p.Y56X mutation in PSENEN. Haplotype analysis confirmed a common ancestral origin for the mutation in all 4 patients. Using qPCR and RNA extracted from patient keratinocytes, we observed a significant decrease in the expression of PSENEN as well as POFUT1 which had previously been implicated in DDD. DDD as well as HS-associated genes have been shown to encode important regulators of Notch signaling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in patient's keratinocytes. The present data confirm the genetic basis of the combined DDD-HS phenotype and suggest that Notch signaling may play a central role in the pathogenesis of this rare condition.
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关键词
Hidradenitis Suppurativa
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