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          Document History for Document ID 539722

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Document Version Version Comment Date Status
539722.0 [No comment] 09.03.2011 14:46 Released

ID: 539722.0, MPI für molekulare Genetik / Research Group Development and Disease
Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome
Authors:Brancati, F.; Fortugno, P.; Bottillo, I.; Lopez, M.; Josselin, E.; Boudghene-Stambouli, O.; Agolini, E.; Bernardini, L.; Bellacchio, E.; Iannicelli, M.; Rossi, A.; Dib-Lachachi, A.; Stuppia, L.; Palka, G.; Mundlos, S.; Stricker, S.; Kornak, U.; Zambruno, G.; Dallapiccola, B.
Language:English
Research Context:This study was supported in part by funding from the Italian Ministry of Health, Ricerca Corrente 2009–2010 (F.B., G.Z., and B.D.).
Date of Publication (YYYY-MM-DD):2010-08-13
Title of Journal:American Journal of Human Genetics
Journal Abbrev.:Am J Hum Genet
Volume:87
Issue / Number:2
Start Page:265
End Page:273
Copyright:© 2010 The American Society of Human Genetics.
Published by Elsevier Ltd. All right reserved..
Review Status:not specified
Audience:Experts Only
Abstract / Description:Ectodermal dysplasias form a large disease family with more than 200 members. The combination of hair and tooth abnormalities, alopecia, and cutaneous syndactyly is characteristic of ectodermal dysplasia-syndactyly syndrome (EDSS). We used a homozygosity mapping approach to map the EDSS locus to 1q23 in a consanguineous Algerian family. By candidate gene analysis, we identified a homozygous mutation in the PVRL4 gene that not only evoked an amino acid change but also led to exon skipping. In an Italian family with two siblings affected by EDSS, we further detected a missense and a frameshift mutation. PVRL4 encodes for nectin-4, a cell adhesion molecule mainly implicated in the formation of cadherin-based adherens junctions. We demonstrated high nectin-4 expression in hair follicle structures, as well as in the separating digits of murine embryos, the tissues mainly affected by the EDSS phenotype. In patient keratinocytes, mutated nectin-4 lost its capability to bind nectin-1. Additionally, in discrete structures of the hair follicle, we found alterations of the membrane localization of nectin-afadin and cadherin-catenin complexes, which are essential for adherens junction formation, and we found reorganization of actin cytoskeleton. Together with cleft lip and/or palate ectodermal dysplasia (CLPED1, or Zlotogora-Ogur syndrome) due to an impaired function of nectin-1, EDSS is the second known "nectinopathy" caused by mutations in a nectin adhesion molecule.
Comment of the Author/Creator:Corresponding author ; Email: f.brancati@css-mendel.it
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Biomedical Sciences, Aging Research Center, Gabriele d'Annunzio University, 66100 Chieti, Italy;
2.Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza Hospital, Mendel Laboratory, 71013 San Giovanni Rotondo, Italy;
3.Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, 00167 Rome, Italy;
4.Inserm Unité Mixte de Recherche 891, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Université de la Méditerranée, 13009 Marseille, France;
5.Dermatology Unit, Aboubakr Belkaid University Hospital, 13000 Tlemcen, Algeria;
6.Department of Dermatology, La Sapienza University, 00161 Rome, Italy;
7.Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.

9Bambino Gesù Children Hospital, IRCCS, 00165 Rome, Italy
Identifiers:ISSN:0002-9297 [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/20691405 [ID No:2]
DOI:10.1016/j.ajhg.2010.07.003. [ID No:3]
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