Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy.
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.
Hassel
David
D
Department of Medicine III, University of Heidelberg, Heidelberg, Germany.
Dahme
Tillman
T
Erdmann
Jeanette
J
Meder
Benjamin
B
Huge
Andreas
A
Stoll
Monika
M
Just
Steffen
S
Hess
Alexander
A
Ehlermann
Philipp
P
Weichenhan
Dieter
D
Grimmler
Matthias
M
Liptau
Henrike
H
Hetzer
Roland
R
Regitz-Zagrosek
Vera
V
Fischer
Christine
C
Nürnberg
Peter
P
Schunkert
Heribert
H
Katus
Hugo A
HA
Rottbauer
Wolfgang
W
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
D008840:Microfilament Proteins; C501659:NEXN protein, human