PUBLICATION
Mutations in ILK, encoding integrin-linked kinase, are associated with arrhythmogenic cardiomyopathy
- Authors
- Brodehl, A., Rezazadeh, S., Williams, T., Munsie, N.M., Liedtke, D., Oh, T., Ferrier, R., Shen, Y., Jones, S.J.M., Stiegler, A.L., Boggon, T.J., Duff, H.J., Friedman, J.M., Gibson, W.T., FORGE Canada Consortium, Childs, S.J., Gerull, B.
- ID
- ZDB-PUB-190227-8
- Date
- 2019
- Source
- Translational research : the journal of laboratory and clinical medicine 208: 15-29 (Journal)
- Registered Authors
- Childs, Sarah J., Liedtke, Daniel
- Keywords
- none
- MeSH Terms
-
- Adolescent
- Amino Acid Sequence
- Animals
- Arrhythmias, Cardiac/genetics*
- Cardiomyopathies/genetics*
- Cell Line
- Exome Sequencing
- Female
- Humans
- Male
- Mutation*
- Mutation, Missense
- Pedigree
- Protein Serine-Threonine Kinases/chemistry
- Protein Serine-Threonine Kinases/genetics*
- Rats
- Sequence Homology, Amino Acid
- Zebrafish/genetics
- PubMed
- 30802431 Full text @ Transl. Res.
Citation
Brodehl, A., Rezazadeh, S., Williams, T., Munsie, N.M., Liedtke, D., Oh, T., Ferrier, R., Shen, Y., Jones, S.J.M., Stiegler, A.L., Boggon, T.J., Duff, H.J., Friedman, J.M., Gibson, W.T., FORGE Canada Consortium, Childs, S.J., Gerull, B. (2019) Mutations in ILK, encoding integrin-linked kinase, are associated with arrhythmogenic cardiomyopathy. Translational research : the journal of laboratory and clinical medicine. 208:15-29.
Abstract
Arrhythmogenic cardiomyopathy is a genetic heart muscle disorder characterized by fibro-fatty replacement of cardiomyocytes leading to life-threatening ventricular arrhythmias, heart failure, and sudden cardiac death. Mutations in genes encoding cardiac junctional proteins are known to cause about half of cases, while remaining genetic causes are unknown. Using exome sequencing, we identified 2 missense variants (p.H33N and p.H77Y) that were predicted to be damaging in the integrin-linked kinase (ILK) gene in 2 unrelated families. The p.H33N variant was found to be de novo. ILK links integrins and the actin cytoskeleton, and is essential for the maintenance of normal cardiac function. Both of the new variants are located in the ILK ankyrin repeat domain, which binds to the first LIM domain of the adaptor proteins PINCH1 and PINCH2. In silico binding studies proposed that the human variants disrupt the ILK-PINCH complex. Recombinant mutant ILK expressed in H9c2 rat myoblast cells shows aberrant prominent cytoplasmic localization compared to the wild-type. Expression of human wild-type and mutant ILK under the control of the cardiac-specific cmlc2 promotor in zebrafish shows that p.H77Y and p.P70L, a variant previously reported in a dilated cardiomyopathy family, cause cardiac dysfunction and death by about 2-3 weeks of age. Our findings provide genetic and functional evidence that ILK is a cardiomyopathy disease gene and highlight its relevance for diagnosis and genetic counseling of inherited cardiomyopathies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping