Human Molecular Genetics Advance Access originally published online on May 27, 2008
Human Molecular Genetics 2008 17(18):2753-2765; doi:10.1093/hmg/ddn160
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Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy
1 Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Med. Klinik m. S. Kardiologie, 13353 Berlin, Germany 2 Experimental and Clinical Research Center (ECRC) at the Max Delbrück Center for Molecular Medicine (MDC), Cardiovascular Genetics, 13125 Berlin, Germany 3 Department of Medicine, University College London, London WC1E 6DD, UK 4 The Randall Division of Cell and Molecular Biophysics and the Cardiovascular Division, King’s College London, London SE1 1UL, UK 5 Bundesinstitut für Risikobewertung – ZEBET, 12277 Berlin, Germany 6 Faculdada de Ciências Médicas da Universidade Nova de Lisboa, 1700-093 Lisbon, Portugal 7 Max-Delbrück-Centrum für Molekulare Medizin (MDC) Berlin-Buch, 13125 Berlin, Germany 8 DRK Kliniken Berlin Köpenick, Medizinische Klinik I, 12559 Berlin, Germany 9 Krankenhaus Reinbek, St Adolfstift, Medizinische Klinik, 21465 Hamburg-Reinbek, Germany 10 Institut für Herz-Kreislaufforschung an der Universität Witten/Herdecke, 44225 Dortmund, Germany 11 Cardiovascular Research Centre, Massachusetts General Hospital, Department of Cell Biology, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02114, USA 12 Charité Universitätsmedizin Berlin, Experimental and Clinical Research Centre (ECRC), Muscle Research Unit, 13125 Berlin, Germany 13 Abteilung Molekulare Zellbiologie, Institut für Zellbiologie, Universität Bonn, 53121 Bonn, Germany 14 Cologne Centre for Genomics and Institute for Genetics, University of Cologne, 50674 Köln, Germany
* To whom correspondence should be addressed at: Charité Universitätsmedizin Berlin, Med. Klinik m. S. Kardiologie, Augustenburger Platz 1, 13353 Berlin, Germany. Tel: +49 30450553055; Fax: +49 30450565955; Email: christian.geier{at}charite.de
Received March 12, 2008; Revised May 1, 2008; Accepted May 21, 2008
Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP’s mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. We also present evidence for mild skeletal muscle disease in affected persons. Our results support the view that HCM is not exclusively a sarcomeric disease and also suggest that impaired mechano-sensory stress signalling might be involved in the pathogenesis of HCM.
Each of these authors contributed equally to this manuscript.
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