Thick filament molecular interfaces play a critical role in the pathogenesis of hypertrophic cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Structural Biology

Background:

• Hypertrophic cardiomyopathy (HCM) is linked to variants in sarcomeric proteins, including myosin heavy chain (MHC), myosin light chains (MYL2, MYL3), and cardiac myosin binding protein-C (cMyBP-C).
• These variants disrupt cardiac function through abnormal contractility, relaxation, and energy use.

Purpose of the Study:

• To structurally map pathogenic and benign missense variants in key HCM genes.
• To investigate the impact of variant location within the cardiac thick filament interactome on disease phenotype.

Main Methods:

• Utilized a cryo-electron microscopy (cryo-EM) atomic model of the human cardiac thick filament.
• Mapped 233 missense variants (MYH7, MYBPC3, MYL2, MYL3) onto the structural model.
• Correlated variant location within molecular interfaces with clinical data.

Main Results:

• Identified 30 molecular interfaces in the thick filament interactome containing HCM variants.
• No benign variants were located within these critical interfaces.
• Pathogenic variants within interfaces were associated with earlier disease onset and adverse patient outcomes compared to those outside interfaces.

Conclusions:

• Variant location within molecular interfaces of the cardiac thick filament is crucial for normal function.
• Structural mapping of variants can improve risk stratification for hypertrophic cardiomyopathy patients.
• Understanding these structural consequences aids in predicting disease severity.