Article abstract
Nature Medicine 15, 1281 - 1288 (2009)
Published online: 1 November 2009 | doi:10.1038/nm.2037
Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy
David Hassel1,9, Tillman Dahme1,9, Jeanette Erdmann2,9, Benjamin Meder1, Andreas Huge3, Monika Stoll3, Steffen Just1, Alexander Hess1, Philipp Ehlermann1, Dieter Weichenhan1, Matthias Grimmler4, Henrike Liptau2, Roland Hetzer5, Vera Regitz-Zagrosek5,6, Christine Fischer7, Peter Nürnberg8, Heribert Schunkert2, Hugo A Katus1 & Wolfgang Rottbauer1
Abstract
Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein. Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure. To evaluate the role of nexilin in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found several mutations in NEXN associated with the disease. Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish. Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations. Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma.
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany.
- Medizinische Klinik II, Universität zu Lübeck, Germany.
- Department of Genetic Epidemiology of Vascular Diseases, Leibniz-Institute for Arteriosclerosis Research at the University of Münster, Münster, Germany.
- Department of Biochemistry, Biocenter at the University of Würzburg, Würzburg, Germany.
- German Heart Center Berlin, Berlin, Germany.
- Center for Cardiovascular Research, Charité, Berlin, Germany.
- Department of Human Genetics, University of Heidelberg, Heidelberg, Germany.
- Cologne Center for Genomics, University of Cologne, Cologne, Germany.
- These authors contributed equally to this work.
Correspondence to: Wolfgang Rottbauer1 e-mail: wolfgang.rottbauer@med.uni-heidelberg.de
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