Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation

Area of Science:

• Biochemistry
• Genetics
• Cardiology

Background:

• Myosin motors are crucial for muscle contraction.
• MYH7 gene variations are linked to hypertrophic cardiomyopathy (HCM), a serious heart condition.
• The precise impact of specific myosin variants on motor function and disease remains unclear.

Purpose of the Study:

• To identify regions of disease enrichment within beta-cardiac myosin.
• To understand how specific myosin variants contribute to hypertrophic cardiomyopathy.
• To correlate variant location with disease onset and severity.

Main Methods:

• Developed computational models of human beta-cardiac myosin across its chemomechanical cycle.
• Analyzed exome sequencing data from large population cohorts.
• Applied a spatial scan statistic to genetic variation in protein 3D space.
• Integrated genetic and phenotypic data from HCM patients.

Main Results:

• Significant enrichment of disease-associated variants found in the converter domain of beta-cardiac myosin.
• A larger enriched region, including the converter domain and myosin mesa, identified for surface-exposed residues.
• HCM patients with variants in these enriched regions exhibited earlier disease onset.

Conclusions:

• Specific regions within beta-cardiac myosin are significantly associated with hypertrophic cardiomyopathy.
• The location of MYH7 variants influences the clinical presentation, particularly age of onset.
• This study offers a framework for integrating structural biology, genomics, and clinical data to study genetic heart diseases.