De Novo Missense Mutations in TNNC1 and TNNI3 Causing Severe Infantile Cardiomyopathy Affect Myofilament Structure...

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Rare pediatric cardiomyopathies, including non-compaction and restrictive types, often present with severe, rapid progression.
• Non-compaction cardiomyopathy involves structural defects and systolic dysfunction, while restrictive cardiomyopathy is characterized by diastolic dysfunction.
• The underlying molecular mechanisms for these conditions, particularly involving cardiac troponin function, remain poorly understood.

Purpose of the Study:

• To compare the molecular and functional effects of two distinct infantile de novo point mutations in TNNC1 (p.cTnC-G34S) and TNNI3 (p.cTnI-D127Y).
• To investigate how these mutations impact cardiac muscle thin filament structure, function, and protein interactions.
• To assess the potential of specific therapeutic agents in ameliorating the molecular defects caused by these mutations.

Main Methods:

• Utilized skinned cardiomyocytes, skinned fibers, and reconstituted thin filaments to assess contractile function.
• Examined the interactions of mutated troponin variants with actin and their inter-subunit dynamics.
• Analyzed the structural integrity of reconstituted thin filaments and investigated the impact on the protein quality control system using patient myocardial tissue.

Main Results:

• Both p.cTnC-G34S and p.cTnI-D127Y mutations induced similar functional and structural impairments in cardiac thin filaments, despite leading to different clinical phenotypes (non-compaction vs. restrictive cardiomyopathy).
• Mutations affected protein quality control mechanisms, as evidenced by findings in patient myocardial tissue for the TnC-G34S mutation.
• The agents levosimendan and (-)-epigallocatechin-3-gallate (EGCg) demonstrated partial stabilization of thin filament integrity and amelioration of contractile function in vitro for both mutations.

Conclusions:

• Infantile de novo mutations in TNNC1 and TNNI3 can cause severe cardiomyopathies with distinct clinical presentations despite shared molecular impairments in cardiac muscle contraction.
• These findings underscore the complexity of genotype-phenotype correlations in pediatric cardiomyopathies.
• Targeting troponin function with agents like levosimendan and EGCg shows potential for therapeutic intervention, though efficacy may vary.