ZFIN ID: ZDB-PUB-091120-10
Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy
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., Nürnberg, P., Schunkert, H., Katus, H.A., and Rottbauer, W.
Date: 2009
Source: Nature medicine   15(11): 1281-1288 (Journal)
Registered Authors: Dahme, Tillmann, Hassel, David, Hess, Alexander, Just, Steffen, Meder, Benjamin, Rottbauer, Wolfgang
Keywords: none
MeSH Terms:
  • Adult
  • Aged
  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Cardiomyopathy, Dilated*/etiology
  • Cardiomyopathy, Dilated*/genetics
  • Cardiomyopathy, Dilated*/pathology
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 1
  • Computational Biology
  • Disease Models, Animal
  • Embryo, Mammalian
  • Family Health
  • Female
  • Genetic Predisposition to Disease/genetics*
  • Humans
  • Male
  • Microfilament Proteins/deficiency
  • Microfilament Proteins/genetics*
  • Middle Aged
  • Muscle Contraction/genetics
  • Muscle Fibers, Skeletal
  • Mutation/genetics*
  • Myocardium/pathology
  • Myocytes, Cardiac/metabolism
  • Myocytes, Cardiac/pathology*
  • Polymorphism, Single Nucleotide/genetics
  • Sarcomeres/genetics*
  • Sarcomeres/physiology
  • Zebrafish
PubMed: 19881492 Full text @ Nat. Med.
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.