RGD Reference Report - Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy. - Rat Genome Database

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

Authors: Hassel, D  Dahme, T  Erdmann, J  Meder, B  Huge, A  Stoll, M  Just, S  Hess, A  Ehlermann, P  Weichenhan, D  Grimmler, M  Liptau, H  Hetzer, R  Regitz-Zagrosek, V  Fischer, C  Nurnberg, P  Schunkert, H  Katus, HA  Rottbauer, W 
Citation: Hassel D, etal., Nat Med. 2009 Nov;15(11):1281-8. doi: 10.1038/nm.2037. Epub 2009 Nov 1.
RGD ID: 8553584
Pubmed: PMID:19881492   (View Abstract at PubMed)
DOI: DOI:10.1038/nm.2037   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Z disc located_inIDA 8553584PMID:19881492UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Nexn  (nexilin (F actin binding protein))


Additional Information