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

Translational Research : the Journal of Laboratory and Clinical Medicine
Andreas BrodehlBrenda Gerull

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 i...Continue Reading

Citations

Aug 23, 2020·International Journal of Molecular Sciences·Seung Hee LeeWon-Ho Kim
Jul 17, 2020·Frontiers in Physiology·Brenda Gerull, Andreas Brodehl
Sep 7, 2019·International Journal of Molecular Sciences·Andreas BrodehlHendrik Milting
Dec 18, 2020·Frontiers in Physiology·Yonghe DingXiaolei Xu
Apr 1, 2021·British Journal of Pharmacology·George BowleyJovana Serbanovic-Canic
Sep 4, 2021·Current Heart Failure Reports·Brenda Gerull, Andreas Brodehl
Nov 20, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Marie-Louise BangJu Chen

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