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

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Item Type:	Article
Title:	Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa
Creators Name:	Ralser, D.J., Basmanav, F.B.Ü., Tafazzoli, A., Wititsuwannakul, J., Delker, S., Danda, S., Thiele, H., Wolf, S., Busch, M., Pulimood, S.A., Altmüller, J., Nürnberg, P., Lacombe, D., Hillen, U., Wenzel, J., Frank, J., Odermatt, B. and Betz, R.C.
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.
Keywords:	Amyloid Precursor Protein Secretases, Nonsense Codon, Genetic Association Studies, Genetic Predisposition to Disease, Hidradenitis Suppurativa, Hyperpigmentation, Membrane Proteins, Genetic Skin Diseases, Papulosquamous Skin Diseases, Animals, Zebrafish
Source:	Journal of Clinical Investigation
ISSN:	0021-9738
Publisher:	American Society for Clinical Investigation
Volume:	127
Number:	4
Page Range:	1485-1490
Date:	3 April 2017
Official Publication:	https://doi.org/10.1172/JCI90667
PubMed:	View item in PubMed

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