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

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Diseases

Background:

• Hypertrophic cardiomyopathy (HCM) is a hereditary heart disorder often caused by sarcomere gene mutations.
• While TNNI3 mutations are linked to HCM, their specific impact on disease severity and progression is not fully understood.
• The relationship between TNNI3 variants and clinical phenotypes requires further investigation.

Purpose of the Study:

• To investigate the pathogenic role of the TNNI3 c.235C > T mutation in hypertrophic cardiomyopathy (HCM).
• To elucidate the underlying molecular mechanisms by which this TNNI3 variant contributes to HCM development.
• To explore the clinical manifestations and disease progression associated with the TNNI3 c.235C > T mutation.

Main Methods:

• Gene sequencing was used to identify pathogenic mutations in an HCM family.
• Clinical assessments including ECG, echocardiography, and cardiac MRI were performed on affected individuals.
• In vitro experiments involved transfecting AC16 human cardiomyocyte cell lines with the TNNI3 c.235C > T mutant plasmid.

Main Results:

• The TNNI3 c.235C > T mutation was identified as the causative variant in the studied HCM family.
• The mutation upregulated hypertrophy markers (ANP, BNP, MYH7), increased cardiomyocyte size, and activated the ERK signaling pathway.
• Impaired mitochondrial function, disrupted metabolism, and increased autophagy and apoptosis were observed in cardiomyocytes with the mutation.

Conclusions:

• The TNNI3 c.235C > T mutation is a pathogenic factor for HCM, presenting with heterogeneous clinical phenotypes.
• This mutation induces myocardial hypertrophy, activates ERK signaling, and exacerbates mitochondrial dysfunction, apoptosis, and autophagy.
• Findings offer insights into HCM mechanisms driven by gene mutations, potentially guiding future treatment strategies.