The structure of the cardiac thick filament helps improve risk assessment of HCM patients

What is it about?

Heart contraction results from the interaction of thick and thin protein filaments. Pathogenic variants in thick filament proteins produce hypertrophic cardiomyopathy that impairs the heartbeat, but the underlying mechanisms are unclear. Here, we map more than 200 pathogenic variants onto an atomic model of the thick filament based on cryo-EM. We find that many variants cluster in the interfaces between thick filament components that underlie normal thick filament structure. Alterations to these interfaces impair filament function, suggesting a mechanistic basis for the abnormal contractility associated with this myopathy. We demonstrate earlier disease onset and adverse outcomes in pathogenic variants within vs. outside of molecular interfaces, emphasizing their importance in normal thick filament function and improving risk assessment of patients.

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Why is it important?

We demonstrate earlier disease onset and adverse outcomes in pathogenic variants within vs. outside of molecular interfaces, emphasizing their importance in normal thick filament function and improving risk assessment of patients.