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

被引:38
作者
Brodehl, Andreas [1 ]
Rezazadeh, Saman [1 ]
Williams, Tatjana [2 ]
Munsie, Nicole M. [3 ]
Liedtke, Daniel [4 ]
Oh, Tracey [5 ]
Ferrier, Raechel [6 ]
Shen, Yaoqing [7 ]
Jones, Steven J. M. [7 ]
Stiegler, Amy L. [8 ]
Boggon, Titus J. [8 ]
Duff, Henry J. [1 ]
Friedman, Jan M. [5 ]
Gibson, William T. [5 ,9 ]
Boycott, K. [10 ]
Friedman, J. [11 ]
Michaud, J. [12 ]
Bernier, F. [13 ]
Brudno, M. [14 ]
Fernandez, B. [15 ]
Knoppers, B. [16 ]
Samuels, M. [12 ]
Scherer, S. [14 ]
Childs, Sarah J. [3 ]
Gerull, Brenda [1 ,2 ]
机构
[1] Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Cardiac Sci, Calgary, AB, Canada
[2] Univ Hosp Wurzburg, Comprehens Heart Failure Ctr, Wurzburg, Germany
[3] Univ Calgary, Alberta Childrens Hosp Res Inst, Dept Biochem & Mol Biol, Calgary, AB, Canada
[4] Julius Maximilians Univ Wurzburg, Inst Human Genet, Wurzburg, Germany
[5] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada
[6] Alberta Hlth Serv, Dept Med Genet, Calgary, AB, Canada
[7] Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada
[8] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA
[9] BC Childrens Hosp Res Inst, Vancouver, BC, Canada
[10] Univ Ottawa, Ottawa, ON, Canada
[11] Univ British Columbia, Vancouver, BC, Canada
[12] Univ Montreal, Montreal, PQ, Canada
[13] Univ Calgary, Calgary, AB, Canada
[14] Univ Toronto, Toronto, ON, Canada
[15] Mem Univ, St John, NF, Canada
[16] McGill Univ, Montreal, PQ, Canada
基金
加拿大健康研究院;
关键词
RIGHT-VENTRICULAR CARDIOMYOPATHY; DILATED CARDIOMYOPATHY; CARDIAC CONTRACTILITY; TARGETED ABLATION; STRUCTURAL BASIS; HEART; PHENOTYPE; GENETICS; PINCH2;
D O I
10.1016/j.trsl.2019.02.004
中图分类号
R446 [实验室诊断]; R-33 [实验医学、医学实验];
学科分类号
1001 ;
摘要
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.P7OL, 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.
引用
收藏
页码:15 / 29
页数:15
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