Match!

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

Published on Jun 1, 2019in Translational Research4.92
· DOI :10.1016/j.trsl.2019.02.004
Andreas Brodehl8
Estimated H-index: 8
(Libin Cardiovascular Institute of Alberta),
Saman Rezazadeh1
Estimated H-index: 1
(Libin Cardiovascular Institute of Alberta)
+ 13 AuthorsBrenda Gerull20
Estimated H-index: 20
(Libin Cardiovascular Institute of Alberta)
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.
  • References (53)
  • Citations (0)
References53
Newest
#1Kristin D. Kernohan (Children's Hospital of Eastern Ontario)H-Index: 12
#2Taila Hartley (Children's Hospital of Eastern Ontario)H-Index: 12
Last.David A. Dyment (Children's Hospital of Eastern Ontario)H-Index: 40
view all 12 authors...
#1Aditya Bhonsale (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 17
#2Anneline S.J.M. te Riele (UU: Utrecht University)H-Index: 17
Last.Hugh Calkins (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 104
view all 17 authors...
#1Monkol Lek (Broad Institute)H-Index: 33
#2Konrad J. Karczewski (Broad Institute)H-Index: 30
Last.Daniel G. MacArthur (Harvard University)H-Index: 52
view all 79 authors...
#1Sofia Hirth (University of Ulm)H-Index: 5
#2Anja Bühler (University of Ulm)H-Index: 3
Last.Steffen Just (University of Ulm)H-Index: 25
view all 7 authors...
#1Andreas Brodehl (Libin Cardiovascular Institute of Alberta)H-Index: 8
#2R. Ferrier (AHS: Alberta Health Services)H-Index: 2
Last.Brenda Gerull (Libin Cardiovascular Institute of Alberta)H-Index: 2
view all 13 authors...
View next paperLaminin-α4 and Integrin-Linked Kinase Mutations Cause Human Cardiomyopathy Via Simultaneous Defects in Cardiomyocytes and Endothelial Cells