Premium
A phenotype combining hidradenitis suppurativa with Dowling–Degos disease caused by a founder mutation in PSENEN
Author(s) -
Pavlovsky M.,
Sarig O.,
EskinSchwartz M.,
Malchin N.,
Bochner R.,
Mohamad J.,
Gat A.,
Peled A.,
Hafner A.,
Sprecher E.
Publication year - 2018
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.16000
Subject(s) - hidradenitis suppurativa , haplotype , genetics , mutation , phenotype , biology , medicine , gene , disease , allele , pathology
Summary Background Dowling–Degos disease ( DDD ), featuring reticulate pigmentation, and familial hidradenitis suppurativa ( HS ) share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The coexistence of the two disorders was recently found to result from mutations in PSENEN , encoding the γ‐secretase subunit protein presenilin enhancer. Objectives To investigate PSENEN mutations in a series of four unrelated patients who presented with combined DDD and HS . Methods Mutation and haplotype analysis of PSENEN by polymerase chain reaction, and cellular assays investigating the Notch signalling pathway. Results Here we report four families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c.168T>G, p.Y56X). Haplotype analysis revealed that the mutation originated from a common ancestor. Genes associated with DDD , as well as HS , have been shown to encode important regulators of Notch signalling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in a patient's keratinocytes. Conclusions The present data confirm the genetic basis of the combined DDD ‐ HS phenotype and suggest that Notch signalling may play a central role in the pathogenesis of this rare condition.