Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy

David Hassel, Tillman Dahme, Jeanette Erdmann, Benjamin Meder, Andreas Huge, Monika Stoll, Steffen Just, Alexander Hess, Philipp Ehlermann, Dieter Weichenhan, Matthias Grimmler, Henrike Liptau, Roland Hetzer, Vera Regitz-Zagrosek, Christine Fischer, Peter Nürnberg, Heribert Schunkert, Hugo A. Katus, Wolfgang Rottbauer*

*Korrespondierende/r Autor/-in für diese Arbeit
77 Zitate (Scopus)

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.
OriginalspracheEnglisch
ZeitschriftNature Medicine
Jahrgang15
Ausgabenummer11
Seiten (von - bis)1281-1288
Seitenumfang8
ISSN1078-8956
DOIs
PublikationsstatusVeröffentlicht - 01.11.2009

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