Novel Mutations in PSENEN Gene in Two Chinese Acne Inversa Families Manifested as Familial Multiple Comedones and Dowling-Degos Disease

Abstract

Background:Acne inversa (AI), also called hidradenitis suppurativa, is a chronic, inflammatory, recurrent skin disease of the hair follicle. Familial AI shows autosomal-dominant inheritance caused by mutations in the γ-secretase genes. This study was aimed to identify the specific mutations in the γ-secretase genes in two Chinese families with AI.Methods:In this study, two Chinese families with AI were investigated. All the affected individuals in the two families mainly manifested with multiple comedones, pitted scars, and a few inflammatory nodules on their face, neck, trunk, axilla, buttocks, upper arms, and thighs. Reticulate pigmentation in the flexures areas resembled Dowling-Degos disease clinically and pathologically. In addition, one of the affected individuals developed anal canal squamous cell carcinoma. Molecular mutation analysis of γ-secretase genes including PSENEN, PSEN1, and NCSTN was performed by polymerase chain reaction and direct DNA sequencing.Results:Two novel mutations of PSENEN gene were identified, including a heterozygous missense mutation c.194T>G (p.L65R) and a splice site mutation c.167-2A>G.Conclusions:The identification of the two mutations could expand the spectrum of mutations in the γ-secretase genes underlying AI and provide valuable information for further study of genotype-phenotype correlations.

A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN

“…This association (DDD‐HS) was first described by Weber et al . in 1990 and subsequently confirmed in numerous case reports …”

“…DDD has been shown to share many clinical features and sometimes to coexist with HS as DDD‐HS. Recently, DDD‐HS has been shown to result from mutations in PSENEN , encoding a critical component of γ‐secretase . The γ‐secretase complex is involved in the regulation of the canonical Notch signalling pathway.…”

“…It is not clear why mutations in PSENEN can cause either isolated HS or DDD‐HS . It could be envisaged that mutations at different sites along the molecule are associated with specific phenotypes.…”

“…Recently, two reports suggested that DDD‐HS may result from mutations in the PSENEN gene . Here, we studied four additional patients who presented with clinical features consistent with both DDD and HS, who were found to carry a founder Notch‐inhibiting mutation in PSENEN .…”

A gene dysfunction module reveals the underlying pathogenesis of hidradenitis suppurativa: An update

“…Table 2 provides a summary of known specific mutations. 6,8,9,11,[14][15][16][17][18][19][20][21][22][23][24][25] In 2011, Meng and colleagues 25 studied a family with follicular occlusion triad and identified an autosomal dominant pattern using 1p21.1-1q25.3, 6q25.1-25.2, D19S911-D19S1170 and 19q13.1-13.2 susceptibility loci; however, evaluation of 19 microsatellite markers for genotyping, linkage analysis and haplotype analysis did not identify a linkage between these sites and the family. Subsequent studies examined mutations in the c-secretase genes NCSTN, PSENEN and PSEN1, as well as the absence of mutant genes, 26 with results suggesting that hidradenitis suppurativa might be a genetically heterogeneous disease.…”