Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction
Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction
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DOI：
10.1038/s41390-018-0162-1
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发表时间：
2018-11-01
影响因子：
3.6
通讯作者：
Ichida, Fukiko
中科院分区：
文献类型：
--
作者：
Takasaki, Asami;Hirono, Keiichi;Ichida, Fukiko
背景：左心室致密化不全(LVNC)是一种遗传异质性的原发性心肌病。本研究的目的是阐明肌节基因变异在LVNC发病机制和预后中的作用。方法：采用DNA直接测序法，对82例确诊为LVNC的日本患者进行了7个肌节蛋白基因突变的筛查。我们在很大比例(27%)的病例中发现了与预后不良相关的变异(p=0.012)，特别是TPM1、Tnnc1和ACTc1的变异(p=0.012)。为了阐明这一病理作用，我们从一位携带TPM1基因Arg178His突变的患者体内培养和研究了人类诱导多能干细胞(HiPSCs)，该患者接受了心脏移植。这些细胞表现出病理改变，原肌球蛋白1定位错误，导致心肌细胞肌节结构的破坏，并损害了钙的处理。基因芯片分析表明，TPM1基因突变导致多种参与心脏发育的基因表达下调，细胞过程正向调节，尤其是钙信号通路。结论：肌节基因在LVNC的发生发展中起到遗传触发作用，调节心脏发育相关基因的表达，或改变疾病的严重程度。
BACKGROUND: Left ventricular noncompaction (LVNC) is a primary cardiomyopathy with heterogeneous genetic origins. The aim of this study was to elucidate the role of sarcomere gene variants in the pathogenesis and prognosis of LVNC.METHODS AND RESULTS: We screened 82 Japanese patients (0-35 years old), with a diagnosis of LVNC, for mutations in seven genes encoding sarcomere proteins, by direct DNA sequencing. We identified variants in a significant proportion of cases (27%), which were associated with poor prognosis (p = 0.012), particularly variants in TPM1, TNNC1, and ACTC1 (p = 0.012). To elucidate the pathological role, we developed and studied human-induced pluripotent stem cells (hiPSCs) from a patient carrying a TPM1 p. Arg178His mutation, who underwent heart transplantation. These cells displayed pathological changes, with mislocalization of tropomyosin 1, causing disruption of the sarcomere structure in cardiomyocytes, and impaired calcium handling. Microarray analysis indicated that the TPM1 mutation resulted in the down-regulation of the expression of numerous genes involved in heart development, and positive regulation of cellular process, especially the calcium signaling pathway.CONCLUSIONS: Sarcomere genes are implicated as genetic triggers in the development of LVNC, regulating the expression of numerous genes involved in heart development, or modifying the severity of disease.