title: Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy.
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.
authors.affiliation: Department of Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Hassel
authors.forename: Tillman
authors.initials: T
authors.lastname: Dahme
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.forename: Andreas
authors.initials: A
authors.lastname: Huge
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.forename: Alexander
authors.initials: A
authors.lastname: Hess
authors.forename: Philipp
authors.initials: P
authors.lastname: Ehlermann
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.forename: Matthias
authors.initials: M
authors.lastname: Grimmler
authors.forename: Henrike
authors.initials: H
authors.lastname: Liptau
authors.forename: Roland
authors.initials: R
authors.lastname: Hetzer
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1; D019295:Computational Biology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics*; D008875:Middle Aged; D009119:Muscle Contraction / Q000235:genetics; D018485:Muscle Fibers, Skeletal; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012518:Sarcomeres / Q000235:genetics* / Q000502:physiology; D015027:Zebrafish
chemical_list: D008840:Microfilament Proteins; C501659:NEXN protein, human