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Transl Res. 2019 Jun;208:15-29. doi: 10.1016/j.trsl.2019.02.004. Epub 2019 Feb 15.

Mutations in ILK, encoding integrin-linked kinase, are associated with arrhythmogenic cardiomyopathy.

Author information

1
Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
2
Comprehensive Heart Failure Center and Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.
3
Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
4
Institute of Human Genetics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
5
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
6
Department of Medical Genetics, Alberta Health Services, Calgary, Alberta, Canada.
7
Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
8
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
9
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
10
Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada; Comprehensive Heart Failure Center and Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany. Electronic address: gerull_b@ukw.de.

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.

PMID:
30802431
DOI:
10.1016/j.trsl.2019.02.004
[Indexed for MEDLINE]

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