Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia
| Autor: | Richard P. Lifton, Lynn M. Boyden, Christine T. Lauren, Kimberly D. Morel, Brittany G. Craiglow, Erin C. Loring, Kaya Bilguvar, Keith A. Choate, Jing Zhou, Ronghua Hu, Amy S. Paller |
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| Jazyk: | angličtina |
| Předmět: |
Male
Pathology Golgi Apparatus Connexin Oculodentodigital dysplasia medicine.disease_cause Biochemistry Connexins Craniofacial Abnormalities 030207 dermatology & venereal diseases 0302 clinical medicine Erythrokeratodermia variabilis Missense mutation Exome Erythrokeratodermia Variabilis Eye Abnormalities Child Exome sequencing Genetics 0303 health sciences Mutation integumentary system Immunohistochemistry 3. Good health Phenotype Child Preschool Disease Progression Female medicine.medical_specialty Foot Deformities Congenital Molecular Sequence Data Dermatology Biology Skin Diseases Article 03 medical and health sciences medicine Humans Amino Acid Sequence Molecular Biology 030304 developmental biology Sequence Homology Amino Acid Tooth Abnormalities Cell Membrane Sequence Analysis DNA Cell Biology medicine.disease Palmoplantar keratoderma Connexin 43 Mutagenesis Site-Directed Syndactyly HeLa Cells |
| Zdroj: | The Journal of investigative dermatology |
| ISSN: | 0022-202X |
| DOI: | 10.1038/jid.2014.485 |
| Popis: | Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1. |
| Databáze: | OpenAIRE |
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