PUBLICATION
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., Nürnberg, P., Schunkert, H., Katus, H.A., and Rottbauer, W.
- ID
- ZDB-PUB-091120-10
- 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.
Citation
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. (2009) Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy. Nature medicine. 15(11):1281-1288.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping