Whole exome sequencing identifies a novel mutation (c.333+2T > C) of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease
Whole exome sequencing identifies a novel mutation (c.333+2T > C) of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease
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DOI：
10.1016/j.gene.2018.01.055
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发表时间：
2018-03-30
期刊：
影响因子：
3.5
通讯作者：
Xiang, Rong
中科院分区：
文献类型：
--
作者：
Fan, Liang-Liang;Huang, Hao;Xiang, Rong
扩张型心肌病（DCM）和心脏传导疾病（CCD）是两类可引起心力衰竭、晕厥甚至心源性猝死（SCD）的疾病。DCM患者可以同时经历CCD。在最近的研究中，已经在DCM和CCD患者中鉴定出一些致病基因和变体，例如α-肌动蛋白-2和TNNI 3相互作用激酶（TNNI 3 K）。在本研究中，我们采用全外显子组测序（WES）的方法，以探索潜在的致病基因，在中国家庭与DCM和CCD。TNNI 3 K的一个新的剪接位点突变（c.333 + 2 T > C）被鉴定并与受影响的家族成员共分离。这种新的突变在200名健康的当地对照中也不存在，并被Mutationtaster预测为致病。剪接位点突变（c.333 + 2 T > C）可能导致TNNI 3 K基因外显子4中的提前终止密码子，并可诱导无义介导的mRNA降解。Real-time qPCR结果也证实，心肌细胞TNNI 3 K mRNA表达水平较对照组明显降低，可能导致心肌结构紊乱和心律失常。在这项研究中，我们报告了DCM和CCD患者中的第三个新的TNNI 3 K突变，这进一步支持了TNNI 3 K在心脏发育中的重要作用，并扩大了TNNI 3 K突变的谱。本研究结果有助于DCM和CCD家系的遗传学诊断和咨询。
Dilated Cardiomyopathy (DCM) and cardiac conduction disease (CCD) are two kinds if diseases that can induce heart failure, syncope and even sudden cardiac death (SCD). DCM patients can experience CCD at the same time. In recent research, some disease-causing genes and variants have been identified in patients with DCM and CCD, such as Alpha-Actinin-2 and TNNI3 Interacting Kinase (TNNI3K). In this study, we employed whole-exome sequencing (WES) to explore the potential causative genes in a Chinese family with DCM and CCD. A novel splice site mutation (c.333 + 2 T > C) of TNNI3K was identified and co-segregated with the affected family members. This novel mutation was also absent in 200 healthy local controls and predicted to be disease-causing by Mutationtaster. The splice site mutation (c.333 + 2 T > C) may result in a premature stop codon in exon 4 of the TNNI3K gene and can induce nonsense-mediated mRNA decay. Real-time qPCR also confirmed that the level of TNNI3K mRNA expression was decreased significantly compared with the controls, which may lead to myocardial structural disorder and arrhythmia. In this study we reported the third novel mutation of TNNI3K in DCM and CCD patients which further supported the important role of TNNI3K in heart development and expanded the spectrum of TNNI3K mutations. The results may contribute to the genetic diagnosis and counseling of families with DCM and CCD.