TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy
TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy
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DOI：
10.1093/hmg/ddu297
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发表时间：
2014-11-01
影响因子：
3.5
通讯作者：
Olson, Timothy M.
中科院分区：
文献类型：
--
作者：
Theis, Jeanne L.;Zimmermann, Michael T.;Olson, Timothy M.
基因定位已经揭示了家族性房颤（AF）、扩张型心肌病（DCM）和混合型心脏表型综合征的多种病因，但这些疾病的分子基础在大多数情况下仍然是特发性的。全外显子组测序（WES）为家族性疾病基因的发现提供了一个强有力的新工具。在这里，这些基因组策略的协同应用确定了房性快速性心律失常、传导系统疾病（CSD）和DCM脆弱性家族综合征的致病突变。一个三代同堂的家族中有7名成员表现出了CSD表达的表型，其中3人在儿童时期表现出CSD和临床显著的心律失常。全基因组连锁分析将两个同样合理的位点定位于染色体1p3和13q12。对两个受影响表兄弟的WES变体进行了筛选，以寻找罕见的、预测有害的位置变体，揭示了一种未报告的杂合错义突变，破坏了TNNI 3K中高度保守的激酶结构域。肌钙蛋白I相互作用激酶中的G526D取代，可能具有最有害的SIFT和Polyphen2评分，导致体外异常肽聚集，并且计算机模拟对接模型预测改变但能量有利的野生型突变体二聚化。突变携带者的心室组织显示DCM的组织病理学特征，TNNI3K蛋白染色减少，具有独特的无定形核和肌浆内含物。总之，突变的TNNI3K，编码心脏特异性激酶，以前显示调节心脏传导和心肌功能的小鼠，是一个家族综合征的电气和肌病性心脏病。鉴定的取代导致TNNI3K聚集缺陷和蛋白质缺乏，暗示显性阴性功能丧失疾病机制。
Locus mapping has uncovered diverse etiologies for familial atrial fibrillation (AF), dilated cardiomyopathy (DCM), and mixed cardiac phenotype syndromes, yet the molecular basis for these disorders remains idiopathic in most cases. Whole-exome sequencing (WES) provides a powerful new tool for familial disease gene discovery. Here, synergistic application of these genomic strategies identified the pathogenic mutation in a familial syndrome of atrial tachyarrhythmia, conduction system disease (CSD), and DCM vulnerability. Seven members of a three-generation family exhibited the variably expressed phenotype, three of whom manifested CSD and clinically significant arrhythmia in childhood. Genome-wide linkage analysis mapped two equally plausible loci to chromosomes 1p3 and 13q12. Variants from WES of two affected cousins were filtered for rare, predicted-deleterious, positional variants, revealing an unreported heterozygous missense mutation disrupting the highly conserved kinase domain in TNNI3K. The G526D substitution in troponin I interacting kinase, with the most deleterious SIFT and Polyphen2 scores possible, resulted in abnormal peptide aggregation in vitro and in silico docking models predicted altered yet energetically favorable wild-type mutant dimerization. Ventricular tissue from a mutation carrier displayed histopathological hallmarks of DCM and reduced TNNI3K protein staining with unique amorphous nuclear and sarcoplasmic inclusions. In conclusion, mutation of TNNI3K, encoding a heart-specific kinase previously shown to modulate cardiac conduction and myocardial function in mice, underlies a familial syndrome of electrical and myopathic heart disease. The identified substitution causes a TNNI3K aggregation defect and protein deficiency, implicating a dominant-negative loss of function disease mechanism.