Truncated titin proteins in dilated cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Protein Biochemistry

Background:

• Truncating variants in the TTN gene (TTNtvs) are the leading cause of non-ischemic dilated cardiomyopathy (DCM).
• The precise mechanism by which TTNtvs cause DCM has been debated, with previous studies failing to detect truncated titin proteins in affected hearts, suggesting haploinsufficiency as the sole cause.
• Reduced levels of full-length titin protein in DCM hearts have not been definitively demonstrated.

Purpose of the Study:

• To investigate the presence and characteristics of truncated titin proteins in human DCM hearts.
• To determine the abundance of full-length titin protein in hearts with TTNtvs.
• To elucidate the combined molecular mechanisms contributing to TTNtv-associated DCM.

Main Methods:

• Analysis of 184 explanted post-transplant DCM hearts using specialized electrophoresis, Western blotting, and unbiased proteomics.
• Allelic phasing to confirm the origin of truncated proteins.
• Transcriptomic profiling and studies on isolated human adult cardiomyocytes.

Main Results:

• Truncated titin proteins were quantitatively detected in human DCM hearts, with sizes corresponding to TTNtvs and encoded by the variant allele.
• Full-length titin protein was found to be less abundant in TTNtv-positive (TTNtv+) compared to TTNtv-negative (TTNtv-) DCM hearts.
• No significant defects in cardiomyocyte contractility or major transcriptomic differences were observed between TTNtv+ and TTNtv- DCM hearts.

Conclusions:

• This study provides direct evidence for the presence of truncated titin protein in human TTNtv+ DCM.
• Reduced levels of full-length titin protein contribute to the disease pathology.
• The findings support a model where both dominant-negative effects and haploinsufficiency of titin play a role in TTNtv-associated DCM pathogenesis.