Journal
NATURE MEDICINE
Volume 15, Issue 11, Pages 1281-U78Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2037
Keywords
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Funding
- Deutsche Forschungsgemeinschaft [Ro2173/1-1, Ro2173/2-1, Ro2173/2-2, Ro2173/3-1]
- Bundesministerium fur Bildung und Forschung [01GS0108, 01GS0420, 01GS0836]
- Postdoc-Fellowship YIA of the medical faculty of the University of Heidelberg
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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.
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