Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma
| Autor: | Hiroshi Shimizu, Toshifumi Nomura, Neil J. Wilson, Moez Gribaa, Sébastien Teissier, Alan D. Irvine, Alan Evans, W.H. Irwin McLean, Sara J. Brown, Mohamed Denguezli, Ali Saad, Mohammad Shboul, Ons Mamaï, Christian Cole, Geoffrey J. Barton, M. Zamiri, John A. McGrath, Colin S. Munro, Jennifer Hirst, Patricia J.C. Dopping-Hepenstal, Frances J.D. Smith, Lobna Boussofara, Mitsuhiro Suehiro, Elizabeth Pohler, David Goudie, Benvon Moran, Bruno Reversade, H. M. Horn, Aileen Sandilands, Christabelle S M Goh, Izumi Konohana, Masashi Akiyama |
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| Přispěvatelé: | Other departments |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Keratinocytes
congenital hereditary and neonatal diseases and abnormalities Haploinsufficiency Biology Article 030207 dermatology & venereal diseases 03 medical and health sciences 0302 clinical medicine Cytosol Genetics Humans Epidermal growth factor receptor skin and connective tissue diseases 030304 developmental biology 0303 health sciences Gene knockdown Cell growth Chromosome Mapping Proteins Pedigree Porokeratosis ErbB Receptors Adaptor Proteins Vesicular Transport Gene Expression Regulation Cancer research biology.protein Carrier Proteins Punctate palmoplantar keratoderma HeLa Cells Protein Binding |
| Zdroj: | Nature genetics Nature genetics, 44(11), 1272-1276. Nature Publishing Group |
| ISSN: | 1061-4036 |
| DOI: | 10.1038/ng.2444 |
| Popis: | Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics(1-3). Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on the palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding alpha- and gamma-adaptin binding protein p34, located at a previously linked locus at 15q22. alpha- and gamma-adaptin binding protein p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicating a role in membrane trafficking. Ultrastructurally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation |
| Databáze: | OpenAIRE |
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