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Mutations in γ-secretase subunit–encoding PSENEN underlie Dowling-Degos disease associated with acne inversa
- Source :
- Journal of Clinical Investigation. 127:1485-1490
- Publication Year :
- 2017
- Publisher :
- American Society for Clinical Investigation, 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 :
- Male
0301 basic medicine
Skin Diseases, Papulosquamous
Medizin
Disease
Biology
medicine.disease_cause
Melanocyte migration
Pathogenesis
030207 dermatology & venereal diseases
03 medical and health sciences
0302 clinical medicine
Hyperpigmentation
medicine
Animals
Genetic Predisposition to Disease
Genetic Association Studies
Zebrafish
Gene knockdown
Mutation
Brief Report
Membrane Proteins
Skin Diseases, Genetic
Hair follicle disorder
General Medicine
equipment and supplies
Phenotype
Hidradenitis Suppurativa
Keratin 5
030104 developmental biology
Codon, Nonsense
Immunology
Female
Amyloid Precursor Protein Secretases
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 127
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....4b32532cd770d168562708761d84680f