Asunto(s)
Mutación del Sistema de Lectura , Glucosiltransferasas/genética , Hiperpigmentación/genética , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Papuloescamosas/genética , Pigmentación de la Piel/genética , Biopsia , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hiperpigmentación/diagnóstico , Hiperpigmentación/enzimología , Japón , Persona de Mediana Edad , Fenotipo , Enfermedades Cutáneas Genéticas/diagnóstico , Enfermedades Cutáneas Genéticas/enzimología , Enfermedades Cutáneas Papuloescamosas/diagnóstico , Enfermedades Cutáneas Papuloescamosas/enzimologíaRESUMEN
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.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/genética , Hidradenitis Supurativa/genética , Hiperpigmentación/genética , Proteínas de la Membrana/genética , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Papuloescamosas/genética , Animales , Codón sin Sentido , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Hidradenitis Supurativa/enzimología , Hiperpigmentación/enzimología , Masculino , Enfermedades Cutáneas Genéticas/enzimología , Enfermedades Cutáneas Papuloescamosas/enzimología , Pez CebraAsunto(s)
Citidina Desaminasa/análisis , Papillomavirus Humano 16 , Infecciones por Papillomavirus/complicaciones , Neoplasias del Pene/enzimología , Enfermedades Cutáneas Papuloescamosas/enzimología , Neoplasias Cutáneas/enzimología , Adulto , Humanos , Masculino , Neoplasias del Pene/virología , Enfermedades Cutáneas Papuloescamosas/virología , Neoplasias Cutáneas/virología , Verrugas/enzimologíaRESUMEN
In the present study, we aim to evaluate the application potential of a combined assay of human telomerase reverse transcriptase (hTERT) and E6 oncoprotein in screening the virus-infected keratinocytes with higher telomerase activity in human papillomaviruses (HPV) 16- and 18-related bowenoid papulosis (BP). HPV16/18 DNA in BP (n = 123) was identified by in situ hybridization, the expression of hTERT and E6 in HPV16/18-related BP (n = 68) was determined by immunohistochemistry. We demonstrated that the expression of hTERT correlated well with that of E6 oncoprotein in HPV16/18-related BP lesions (Spearman rho = 0.868, P < 0.01). Furthermore, the majority of keratinocytes with positive nuclear staining for hTERT or E6 in the consecutive sections of each HPV16/18-related BP lesion showed nuclear paleomorphism or nuclear mitosis. In conclusion, we suggested that a combined assay of hTERT and E6 oncoprotein can be used to screen the HPV-infected keratinocytes with higher telomerase activity in HPV16-related and HPV18-related BP lesions.
