Zhang Lai, Ding Fengzhi, Ren Zhongyuan, Cheng Weili, Dai He, Liang Qing, Kong Fanling, Xu Wenjing, Wang Minghui, Zhang Yuqing, Tao Qin
Department of Cardiology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, 211100, China.
Department of Physiology, Wannan Medical College, Wuhu, Anhui, 241000, China.
Int J Cardiol. 2025 Jan 15;419:132627. doi: 10.1016/j.ijcard.2024.132627. Epub 2024 Oct 18.
Hypertrophic cardiomyopathy (HCM) is typically manifested as a hereditary disorder, with 30 %-60 % of cases linked to cardiac sarcomere gene mutations. Despite numerous identified TNNI3 mutations associated with HCM, their severity, prevalence, and disease progression vary. The link between TNNI3 variants and phenotypes remains largely unexplored. This study aims to elucidate the impact of the TNNI3 c.235C > T mutation on HCM through clinical research and cell experiments and to explore its mechanism in HCM development.
We screened an HCM family for pathogenic gene mutations using gene sequencing. The proband and family members were assessed through electrocardiography, echocardiography, and cardiac MRI, and a pedigree map was created for disease prediction analysis. Mutant plasmids were constructed with the TNNI3 c.235C > T mutation and transfected into the AC16 human cardiomyocyte cell line to investigate the mutation's effects.
The TNNI3 c.235C > T mutation was identified as the disease-causing variant in the family. This mutation led to the upregulation of hypertrophy-associated genes ANP, BNP, and MYH7, increased cardiomyocyte size, and activation of the ERK signaling pathway. Further investigations revealed that the TNNI3 c.235C > T mutation impaired mitochondrial function, disrupted cardiomyocyte metabolism, and increased cellular autophagy and apoptosis.
The TNNI3 c.235C > T gene mutation may be a pathogenic factor for HCM, showing heterogeneous features and clinical phenotypes. This mutation induces myocardial hypertrophy, activates the ERK signaling pathway, and exacerbates mitochondrial dysfunction, apoptosis, and autophagy in cardiomyocytes. These findings provide insights into the mechanism of HCM caused by gene mutations and may inform HCM treatment strategies.
肥厚型心肌病（HCM）通常表现为一种遗传性疾病，30% - 60%的病例与心脏肌节基因突变有关。尽管已发现众多与HCM相关的TNNI3突变，但其严重程度、患病率和疾病进展各不相同。TNNI3变异与表型之间的联系在很大程度上仍未得到探索。本研究旨在通过临床研究和细胞实验阐明TNNI3基因c.235C>T突变对HCM的影响，并探讨其在HCM发生发展中的机制。
我们采用基因测序对一个HCM家系进行致病基因突变筛查。通过心电图、超声心动图和心脏磁共振成像对先证者及其家庭成员进行评估，并绘制系谱图以进行疾病预测分析。构建携带TNNI3基因c.235C>T突变的突变体质粒，并将其转染至AC16人心肌细胞系中，以研究该突变的影响。
TNNI3基因c.235C>T突变被确定为该家系中的致病变异。此突变导致肥厚相关基因ANP、BNP和MYH7上调，心肌细胞大小增加，并激活ERK信号通路。进一步研究表明，TNNI3基因c.235C>T突变损害线粒体功能，扰乱心肌细胞代谢，并增加细胞自噬和凋亡。
TNNI3基因c.235C>T突变可能是HCM的致病因素，呈现出异质性特征和临床表型。该突变诱导心肌肥厚，激活ERK信号通路，并加剧心肌细胞的线粒体功能障碍、凋亡和自噬。这些发现为基因突变导致HCM的机制提供了见解，并可能为HCM治疗策略提供参考。
