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          Document History for Document ID 447542

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Document Version Version Comment Date Status
447542.0 [No comment] 11.02.2010 11:37 Released

ID: 447542.0, MPI für molekulare Genetik / Research Group Development and Disease
Mutations in PYCR1 cause cutis laxa with progeroid features
Authors:Reversade, Bruno; Escande-Beillard, Nathalie; Dimopoulou, Aikaterini; Fischer, Björn; Chng, Serene C.; Li, Yun; Shboul, Mohammad; Tham, Puay-Yoke; Kayserili, Hülya; Al-Gazali, Lihadh; Shahwan, Monzer; Brancati, Francesco; Lee, Hane; O'Connor, Brian D.; Schmidt-von Kegler, Mareen; Merriman, Barry; Nelson, Stanley F.; Masri, Amira; Alkazaleh, Fawaz; Guerra, Deanna; Ferrari, Paola; Nanda, Arti; Rajab, Anna; Markie, David; Gray, Mary; Nelson, John; Grix, Arthur; Sommer, Annemarie; Savarirayan, Ravi; Janecke, Andreas R.; Steichen, Elisabeth; Sillence, David; Haußer, Ingrid; Budde, Birgit; Nürnberg, Gudrun; Nürnberg, Peter; Seemann, Petra; Kunkel, Désirée; Zambruno, Giovanna; Dallapiccola, Bruno; Schuelke, Markus; Robertson, Stephen; Hamamy, Hanan; Wollnik, Bernd; Van Maldergem, Lionel; Mundlos, Stefan; Kornak, Uwe
Language:English
Date of Publication (YYYY-MM-DD):2009-09
Title of Journal:Nature Genetics
Journal Abbrev.:Nature Genet
Volume:41
Start Page:1016
End Page:1021
Copyright:© 2009 Nature Publishing Group
Review Status:not specified
Audience:Experts Only
Abstract / Description:Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation1, 2, 3. Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.
Comment of the Author/Creator:email: bruno@reversade.com
email: stefan.mundlos@charite.de
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:Institute of Medical Biology, A*STAR, Singapore, Singapore
Institute of Medical Genetics, Charité Universitaetsmedizin Berlin, Germany
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
Medical Genetics Department, Istanbul Medical Faculty, University of Istanbul, Turkey
Department of Paediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan
Ospedale Casa Sollievo della Sofferenza (CSS), San Giovanni Rotondo and Istituto CSS-Mendel, Rome, Italy
Centro Studi Invecchiamento (Ce.S.I.), Department of Biomedical Sciences, Gabriele d'Annunzio University, Chieti, Italy
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
Departments of Pediatrics, Obstetrics and Gynecology, Faculty of Medicine, The University of Jordan, Amman, Jordan
Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
Department of Pediatrics, University of Modena and Reggio Emilia, Modena, Italy
As'ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City, Kuwait
Genetic Unit, Directorate General of Health Affairs, Ministry of Health, Muscat, Sultanate of Oman
Department of Pathology, University of Otago, Dunedin, New Zealand
Genetic Services of Western Australia, King Edward Memorial Hospital for Women, Perth, Australia
The Permanente Medical Group, Sacramento, California, USA
The Ohio State University College of Medicine and Nationwide Children's Hospital, Molecular and Human Genetics, Columbus, Ohio, USA
University of Melbourne, Murdoch Childrens Research Institute, Royal Children's Hospital, and Genetic Health Services Victoria, Parkville, Victoria, Australia
Division of Clinical Genetics, Innsbruck Medical University, Innsbruck, Austria
Klinik fuer Kinder- und Jugendheilkunde, Universitaet Innsbruck, Innsbruck, Austria
Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
Universitaets-Hautklinik Heidelberg, Heidelberg, Germany
Cologne Center for Genomics, Universität zu Köln, Germany
Berlin-Brandenburg Center for Regenerative Therapies, Charité Universitaetsmedizin Berlin, Germany
Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitaetsmedizin Berlin, Germany
Department of Paediatrics and Child Health, University of Otago, Dunedin, New Zealand
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Institute of Human Genetics, University of Cologne, Cologne, Germany
Centre de Génétique Humaine, Centre Hospitalier Universitaire du Sart-Tilman, Université de Liège, Liège, Belgium
Identifiers:DOI:10.1038/ng.413
ISSN:1061-4036
URL:http://www.nature.com/ng/journal/v41/n9/pdf/ng.413...