Year: 2018
Type: article
Study design: Observational Study
Abstract: Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers. Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress. Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins. These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders.
Authors: Sabine Duchatelet, Lynn M. Boyden, Akemi Ishida-Yamamoto, Jing Zhou, Laure Guibbal, Ronghua Hu, Young H. Lim, Christine Bole-Feysot, Patrick Nitschké, Fernando Santos-Simarro, Raul de Lucas, Leonard M. Milstone, Vanessa Gildenstern, Yolanda R. Helfrich, Laura D. Attardi, Richard P. Lifton, Keith A. Choate, Alain Hovnanian
Institutions: Inserm, Institut des Maladies Génétiques Imagine, Université Paris Descartes, Yale University, Asahikawa Medical University, Asahikawa University, Hospital Universitario La Paz, Phoenix Children's Hospital, University of Michigan, Stanford Medicine, Stanford University, Hôpital Necker-Enfants Malades
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,800
Funders: Foundation for Ichthyosis and Related Skin Types, Yale University, Institut des maladies génétiques Imagine, Ministry of Education, Culture, Sports, Science and Technology, Fondation ARC pour la Recherche sur le Cancer, National Institutes of Health, Japan Society for the Promotion of Science, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: Yale Center for Mendelian Disorders, G1730565090, High Performance Computing Instrumentation for the Yale Center for Genome Analysi, Medical Scientist Training Program, Corneodesmosomal abnormality in skin barrier defects, G9000152359, Genetics and Pathobiology of Disorders of Keratinization
OpenAlex ID: W2897925364