Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant

IF 3.2 2区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS International journal of cardiology Pub Date : 2024-10-18 DOI:10.1016/j.ijcard.2024.132627
Lai Zhang , Fengzhi Ding , Zhongyuan Ren , Weili Cheng , He Dai , Qing Liang , Fanling Kong , Wenjing Xu , Minghui Wang , Yuqing Zhang , Qin Tao
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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.
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肥厚型心肌病相关 TNNI3 c.235C > T 变异的致病机制。
背景:肥厚型心肌病(HCM)通常表现为遗传性疾病,30%-60%的病例与心肌肌节基因突变有关。尽管已发现许多与 HCM 相关的 TNNI3 基因突变,但其严重程度、发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讨。本研究旨在通过临床研究和细胞实验阐明 TNNI3 c.235C > T 突变对 HCM 的影响,并探索其在 HCM 发病中的机制:方法:我们通过基因测序筛选了一个 HCM 家族的致病基因突变。方法:我们利用基因测序技术筛选了一个 HCM 家族的致病基因突变,并通过心电图、超声心动图和心脏核磁共振成像对原告和家族成员进行了评估,绘制了血统图,用于疾病预测分析。构建了具有 TNNI3 c.235C > T 突变的突变质粒,并将其转染至 AC16 人类心肌细胞系,以研究该突变的影响:结果:TNNI3 c.235C > T 突变被确定为该家族的致病变异。该突变导致肥大相关基因 ANP、BNP 和 MYH7 上调,心肌细胞体积增大,ERK 信号通路被激活。进一步研究发现,TNNI3 c.235C > T 突变损害了线粒体功能,破坏了心肌细胞的新陈代谢,增加了细胞自噬和凋亡:TNNI3 c.235C > T 基因突变可能是 HCM 的致病因素之一,表现出不同的特征和临床表型。该基因突变可诱导心肌肥厚,激活 ERK 信号通路,并加剧心肌细胞的线粒体功能障碍、细胞凋亡和自噬。这些发现有助于深入了解基因突变导致 HCM 的机制,并为 HCM 治疗策略提供参考。
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来源期刊
International journal of cardiology
International journal of cardiology 医学-心血管系统
CiteScore
6.80
自引率
5.70%
发文量
758
审稿时长
44 days
期刊介绍: The International Journal of Cardiology is devoted to cardiology in the broadest sense. Both basic research and clinical papers can be submitted. The journal serves the interest of both practicing clinicians and researchers. In addition to original papers, we are launching a range of new manuscript types, including Consensus and Position Papers, Systematic Reviews, Meta-analyses, and Short communications. Case reports are no longer acceptable. Controversial techniques, issues on health policy and social medicine are discussed and serve as useful tools for encouraging debate.
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