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Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2017 Apr 03; Vol. 127 (4), pp. 1485-1490. Date of Electronic Publication: 2017 Mar 13. - Publication Year :
- 2017
-
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.
- Subjects :
- Animals
Codon, Nonsense
Female
Genetic Association Studies
Genetic Predisposition to Disease
Hidradenitis Suppurativa enzymology
Hyperpigmentation enzymology
Male
Skin Diseases, Genetic enzymology
Skin Diseases, Papulosquamous enzymology
Zebrafish
Amyloid Precursor Protein Secretases genetics
Hidradenitis Suppurativa genetics
Hyperpigmentation genetics
Membrane Proteins genetics
Skin Diseases, Genetic genetics
Skin Diseases, Papulosquamous genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 127
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 28287404
- Full Text :
- https://doi.org/10.1172/JCI90667