期刊
HEART RHYTHM
卷 16, 期 1, 页码 98-105出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2018.07.015
关键词
Conduction disease; Dilated cardiomyopathy; Genetics; Kinase; Rare variant; Supraventricular tachycardia; TNNI3K
资金
- Netherlands Heart Foundation (CVON-PREDICT project)
- CVON-RESCUED
- AMC PhD Fellowship
- Thailand Research Fund
- Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program
BACKGROUND Rare genetic variants in TNNI3K encoding troponin-I interacting kinase have been linked to a distinct syndrome consisting primarily of supraventricular tachycardias and variably expressed conduction disturbance and dilated cardiomyopathy in 2 families. OBJECTIVE The purpose of this study was to identify new genetic variants associated with inherited supraventricular tachycardias, cardiac conduction disease, and cardiomyopathy. METHODS We conducted next generation sequencing in 3 independent multigenerational families with atrial/junctional tachycardia with or without conduction disturbance, dilated cardiomyopathy, and sudden death. We also assessed the effect of identified variant on protein autophosphorylation. RESULTS In this study, we uncovered the same ultra-rare genetic variant in TNNI3K (c.2302G>A, p.Glu768Lys), which co-segregated with disease features in all affected individuals (n = 23) from all 3 families. TNNI3K harboring the TNNI3K-p.Glu768Lys variant displayed enhanced kinase activity, in line with expectations from previous mouse studies that demonstrated increased conduction indices and procardiomyopathic effects with increased levels of Tnni3k. CONCLUSION This study corroborates further the causal link between rare genetic variation in TNNI3K and this distinct complex phenotype, and points to enhanced kinase activity of TNNI3K as the underlying pathobiological mechanism.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据