ArticleProceedings of the National Academy of Sciences of the United States of America2016
Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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78 citing papers in PubMed, 128 citations in OpenAlex.
- Probabilistic mapping of sub-genic intolerance reveals functional and disease-critical protein regions.bioRxiv : the preprint server for biology · 2026Article
- Force-Induced Ankle Opening Reveals Mechanical Stabilization of the Ankle of Human β-Cardiac Myosin.ACS nano · 2026Article
- The hypertrophic cardiomyopathy mutation G768R makes cardiac myosin a high duty ratio motor.bioRxiv : the preprint server for biology · 2026Article
- Genetics in Hypertrophic Cardiomyopathy: An Evolving Clinical Landscape.Cardiac failure review · 2026Review
- Pediatric dilated cardiomyopathy and the progression to heart failure: mechanisms and interventions focusing on the "gene-inflammation-metabolism" axis.Frontiers in cardiovascular medicine · 2026Review
- Hypertrophic cardiomyopathy: comprehensive insights into pathogenic genes and genotype-phenotype associations.Frontiers in cell and developmental biology · 2026Review
- A combined genomic arrhythmia propensity score delineates cumulative risk.Cell reports. Medicine · 2025Article
- Relationship between genotype and clinical phenotype of hypertrophic cardiomyopathy.World journal of cardiology · 2025Review
- Molecular mechanisms and intervention approaches of heart failure (Review).International journal of molecular medicine · 2025Review
- Recent progress on nanotechnologies for enhancing blood-brain barrier permeability.Smart molecules : open access · 2025Review
- Article
- Interacting myosin head dynamics and their modification by 2'-deoxy-ADP.Biophysical journal · 2024Article
- Reassessing the unifying hypothesis for hypercontractility caused by myosin mutations in hypertrophic cardiomyopathy.The EMBO journal · 2024Review
- Dynamics of the Pre-Powerstroke Myosin Lever Arm and the Effects of Omecamtiv Mecarbil.International journal of molecular sciences · 2024Article
- Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy.Circulation. Genomic and precision medicine · 2024Article
- MYH7 in cardiomyopathy and skeletal muscle myopathy.Molecular and cellular biochemistry · 2024Review
- Exploring Hypertrophic Cardiomyopathy Biomarkers through Integrated Bioinformatics Analysis: Uncovering Novel Diagnostic Candidates.Cardiology research and practice · 2024Article
- Age and Sex Differences in the Genetics of Cardiomyopathy.Journal of cardiovascular translational research · 2023Article
- CRISPRing the hypertrophic cardiomyopathy: correcting one pathogenic variant at a time.Signal transduction and targeted therapy · 2023Article
- Conformational changes linked to ADP release from human cardiac myosin bound to actin-tropomyosin.The Journal of general physiology · 2023Article
18 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 9 institutions in 4 countries.
Funding
Abstract
Myosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within β-cardiac myosin. We first developed computational models of the human β-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.