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          Institute: MPI für molekulare Genetik     Collection: Research Group Development and Disease     Display Documents

ID: 447495.0, MPI für molekulare Genetik / Research Group Development and Disease
Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival
Authors:Hucthagowder, Vishwanathan; Morava, Eva; Kornak, Uwe; Lefeber, Dirk J.; Fischer, Björn; Dimopoulou, Aikaterini; Aldinger, Annika; Choi, Jiwon; Davis, Elaine C.; Abuelo, Dianne N.; Adamowicz, Maciej; Al-Aama, Jumana; Basel-Vanagaite, Lina; Fernandez, Bridget; Greally, Marie T.; Gillessen-Kaesbach, Gabriele; Kayserili, Hulya; Lemyre, Emmanuelle; Tekin, Mustafa; Türkmen, Seval; Tuysuz, Beyhan; Yüksel-Konuk, Berrin; Mundlos, Stefan; Van Maldergem, Lionel; Wevers, Ron A.; Urban, Zsolt
Date of Publication (YYYY-MM-DD):2009-06
Title of Journal:Human Molecular Genetics
Journal Abbrev.:Hum Mol Genet
Issue / Number:12
Start Page:2149
End Page:2165
Copyright:© The Author 2009
Review Status:not specified
Audience:Experts Only
Abstract / Description:Autosomal recessive cutis laxa type 2 (ARCL2), a syndrome of growth and developmental delay and redundant, inelastic skin, is caused by mutations in the a2 subunit of the vesicular ATPase H+-pump (ATP6V0A2). The goal of this study was to define the disease mechanisms that lead to connective tissue lesions in ARCL2. In a new cohort of 17 patients, DNA sequencing of ATP6V0A2 detected either homozygous or compound heterozygous mutations. Considerable allelic and phenotypic heterogeneity was observed, with a missense mutation of a moderately conserved residue p.P87L leading to unusually mild disease. Abnormal N- and/or mucin type O-glycosylation was observed in all patients tested. Premature stop codon mutations led to decreased ATP6V0A2 mRNA levels by destabilizing the mutant mRNA via the nonsense-mediated decay pathway. Loss of ATP6V0A2 either by siRNA knockdown or in ARCL2 cells resulted in distended Golgi cisternae, accumulation of abnormal lysosomes and multivesicular bodies. Immunostaining of ARCL2 cells showed the accumulation of tropoelastin (TE) in the Golgi and in large, abnormal intracellular and extracellular aggregates. Pulse–chase studies confirmed impaired secretion and increased intracellular retention of TE, and insoluble elastin assays showed significantly reduced extracellular deposition of mature elastin. Fibrillin-1 microfibril assembly and secreted lysyl oxidase activity were normal in ARCL2 cells. TUNEL staining demonstrated increased rates of apoptosis in ARCL2 cell cultures. We conclude that loss-of-function mutations in ATP6V0A2 lead to TE aggregation in the Golgi, impaired clearance of TE aggregates and increased apoptosis of elastogenic cells.
Comment of the Author/Creator:email:
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:Department of Pediatrics, Department of Genetics, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8208, St Louis, MO 63110, USA
Department of Pediatrics, Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Centre, Nijmegen 6525GA, The Netherlands
Institute for Medical Genetics, Charité Universitätsmedizin, Berlin 13353, Germany
Department of Anatomy and Cell Biology, McGill University, Montreal, Canada H3A 2B2
Department of Pediatrics, Rhode Island Hospital, Hasbro Children’s Hospital and Brown University School of Medicine, Providence, RI 02903, USA
Department of Biochemistry and Experimental Medicine, The Children’s Memorial Health Institute, Warsaw 04730, Poland Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21486, Saudi Arabia
Schneider Children's Medical Center of Israel and Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49202, Israel
Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel
Medical Genetics Program, Eastern Health, St John’s, Canada A1B 3V6
The National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland
Institut für Humangenetik, Universität zu Lübeck, Lübeck 23538, Germany
Istanbul Medical Faculty, Medical Genetics Department, Istanbul University, Istanbul 34390, Turkey
Service de Génétique Médicale, CHU-Ste-Justine, Montreal, Quebec, Canada
Department of Pediatrics, Ankara University School of Medicine, Ankara 06100, Turkey
Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul 34452, Turkey
Centre de Génétique Humaine, Centre Hospitalier Universitaire du Sart-Tilman, Université de Liège, Liège 4000, Belgium
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