Journal Article

<i>Beyond the sarcomere: CSRP3</i> mutations cause hypertrophic cardiomyopathy

Christian Geier, Katja Gehmlich, Elisabeth Ehler, Sabine Hassfeld, Andreas Perrot, Katrin Hayess, Nuno Cardim, Katrin Wenzel, Bettina Erdmann, Florian Krackhardt, Maximilian G. Posch, Angelika Bublak, Herbert Nägele, Thomas Scheffold, Rainer Dietz, Kenneth R. Chien, Simone Spuler, Dieter O. Fürst, Peter Nürnberg and Cemil Özcelik

in Human Molecular Genetics

Volume 17, issue 18, pages 2753-2765
Published in print September 2008 | ISSN: 0964-6906
Published online May 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn160
Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy

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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.

Journal Article.  6948 words.  Illustrated.

Subjects: Genetics and Genomics

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