Mutations in γ-secretase subunit–encoding PSENEN underlie Dowling-Degos disease associated with acne inversa

Abstract

Dowling-Degos disease (DDD) is an autosomal-dominant disorder of skin pigmentation associated with mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1), or protein O-glucosyltransferase 1 (POGLUT1). Here, we have identified 6 heterozygous truncating mutations in PSENEN, encoding presenilin enhancer protein 2, in 6 unrelated patients and families with DDD in whom mutations in KRT5, POFUT1, and POGLUT1 have been excluded. Further examination revealed that the histopathologic feature of follicular hyperkeratosis distinguished these 6 patients from previously studied individuals with DDD. Knockdown of psenen in zebrafish larvae resulted in a phenotype with scattered pigmentation that mimicked human DDD. In the developing zebrafish larvae, in vivo monitoring of pigment cells suggested that disturbances in melanocyte migration and differentiation underlie the DDD pathogenesis associated with PSENEN. Six of the PSENEN mutation carriers presented with comorbid acne inversa (AI), an inflammatory hair follicle disorder, and had a history of nicotine abuse and/or obesity, which are known trigger factors for AI. Previously, PSENEN mutations were identified in familial AI, and comanifestation of DDD and AI has been reported for decades. The present work suggests that PSENEN mutations can indeed cause a comanifestation of DDD and AI that is likely triggered by predisposing factors for AI. Thus, the present report describes a DDD subphenotype in PSENEN mutation carriers that is associated with increased susceptibility to AI.

Hidradenitis suppurativa of the nape: Description of an atypical phenotype related to severe early‐onset disease in men

“…Histopathological study of skin biopsies of patients with DDD are consistent with epithelial strands in an “antler‐like pattern” . Recently, several mutations in DDD have been described …”

“…The association between HS and DDD has been previously described. A common pathogenic pathway involving γ‐secretase subunit‐encoding PSENEN underlies this association . Whereas only 3% of patients with HS without nape involvement had DDD, 23% of the patients with HS involving the nape had DDD ( P < 0.01).…”

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 …”

“…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 .…”

Atypical presentation of Dowling-Degos disease with novel and recurrent mutations in POFUT1

“…Dowling–Degos disease (DDD) (MIM: 179850, 615327, 615674 and 615696) is an autosomal dominant genodermatosis, characterized by reticulate hyperpigmentation and small dark‐brown hyperkeratotic papules, predominating in flexures and skin folds . Genetically, DDD shows heterogeneity, with four causative genes ( KRT5 , POFUT1 , POGLUT1 and PSENEN ) reported …”