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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引用次数: 0
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.
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.