Mutations in ILK, encoding integrin-linked kinase, are associated with arrhythmogenic cardiomyopathy
| Autor: | Tatjana Williams, Daniel Liedtke, Henry J. Duff, Nicole M. Munsie, Jan M. Friedman, Saman Rezazadeh, William T. Gibson, Brenda Gerull, Raechel A. Ferrier, Steven J.M. Jones, Yaoqing Shen, Amy L. Stiegler, Titus J. Boggon, Andreas Brodehl, Tracey Oh, Sarah J. Childs |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Adolescent Mutant Mutation Missense Cardiomyopathy Protein Serine-Threonine Kinases Biology Article Cell Line 03 medical and health sciences 0302 clinical medicine Physiology (medical) Exome Sequencing medicine Animals Humans Missense mutation Integrin-linked kinase Amino Acid Sequence Zebrafish Exome sequencing Sequence Homology Amino Acid Biochemistry (medical) Public Health Environmental and Occupational Health Arrhythmias Cardiac Dilated cardiomyopathy General Medicine medicine.disease Actin cytoskeleton Pedigree Rats 3. Good health Cell biology 030104 developmental biology 030220 oncology & carcinogenesis Mutation embryonic structures biology.protein Female Ankyrin repeat Cardiomyopathies |
| Zdroj: | Transl Res |
| ISSN: | 1931-5244 |
| Popis: | 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 two missense variants (p.H33N; p.H77Y) that were predicted to be damaging in the integrin-linked kinase (ILK) gene in two 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 wildtype. Expression of human wild-type and mutant ILK under the control of the cardiac-specific cmlc2 promotor in ipebrafish 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 counselling of inherited cardiomyopathies. |
| Databáze: | OpenAIRE |
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