Mutations in ILK, encoding integrin-linked kinase, are associated with arrhythmogenic cardiomyopathy
Mutations in ILK, encoding integrin-linked kinase, are associated with arrhythmogenic cardiomyopathy
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DOI：
10.1016/j.trsl.2019.02.004
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发表时间：
2019-06-01
影响因子：
7.8
通讯作者：
Gerull, Brenda
中科院分区：
文献类型：
--
作者：
Brodehl, Andreas;Rezazadeh, Saman;Gerull, Brenda
致心律失常性心肌病是一种遗传性心肌疾病，其特征是心肌细胞的纤维脂肪替代，导致危及生命的室性心律失常、心力衰竭和心源性猝死。已知编码心脏连接蛋白的基因突变导致约一半的病例，而其余的遗传原因尚不清楚。使用外显子组测序，我们确定了2个错义突变体（p.H33N和p.H77Y），预计在2个不相关的家庭中的整合素连接激酶（ILK）基因的损害。发现p.H33N变异体是新生的。ILK连接整联蛋白和肌动蛋白细胞骨架，并且对于维持正常心脏功能是必需的。这两种新的变体都位于ILK锚蛋白重复结构域中，该结构域与接头蛋白PINCH 1和PINCH 2的第一个LIM结构域结合。计算机模拟结合研究表明，人类变体破坏了ILK-PINCH复合物。在H9 c2大鼠成肌细胞中表达的重组突变体ILK与野生型相比显示异常突出的细胞质定位。在斑马鱼中，在心脏特异性cmlc 2启动子的控制下，人野生型和突变型ILK的表达表明，p.H77Y和p.P7OL（先前在扩张型心肌病家族中报道的变体）在约2-3周龄时引起心功能障碍和死亡。我们的研究结果提供了遗传和功能的证据，ILK是一种心肌病基因，并强调其相关性的诊断和遗传咨询的遗传性心肌病。
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.