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Clinically Linked Mutations in the Central Domains of Cardiac Myosin-Binding Protein C with Distinct Phenotypes Show
Naveed Ahmed Nadvi1, Katharine A Michie1, Ann H Kwan1
1School of Molecular Bioscience, The University of Sydney, NSW 2006, Australia.
Insights
Structural changes in cardiac myosin-binding protein C (cMyBP-C) due to hypertrophic cardiomyopathy (HCM) mutations were analyzed. Two mutations disrupt protein folding, while another affects interactions within the sarcomere, impacting disease presentation.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Protein Structure-Function Relationships
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease.
- Cardiac myosin-binding protein C (cMyBP-C) is crucial for sarcomere structure and function.
- Missense mutations in cMyBP-C are a common cause of HCM.
Purpose of the Study:
- To investigate the structural consequences of three specific cMyBP-C mutations linked to HCM.
- To correlate structural disruptions with observed disease phenotypes.
- To enhance understanding of cMyBP-C's role in cardiac function and HCM pathogenesis.
Main Methods:
- Small-angle scattering (SAS)
- Infrared spectroscopy (IR)
- Nuclear magnetic resonance (NMR) spectroscopy
- Bioinformatics and computational modeling
Main Results:
- Experimental data generally supported bioinformatics predictions.
- Mutations D745G and P873H were found to disrupt cMyBP-C domain folding.
- Mutation R820Q appears solvent-exposed, suggesting altered sarcomeric interactions.
- Distinct disease phenotypes correlate with each mutation's specific structural impact.
Conclusions:
- Structural alterations in cMyBP-C domains are directly linked to HCM.
- Understanding these structural effects provides insight into HCM development.
- This study highlights key structural features essential for normal cMyBP-C function.
Abstract:
The structural effects of three missense mutations clinically linked to hypertrophic cardiomyopathy (HCM) and located in the central domains of cardiac myosin-binding protein C (cMyBP-C) have been determined using small-angle scattering, infrared spectroscopy, and nuclear magnetic resonance spectroscopy. Bioinformatics and modeling were used to initially predict the expected structural impacts and assess the broader implications for function based on sequence conservation patterns. The experimental results generally affirm the predictions that two of the mutations (D745G, P873H) disrupt domain folding, while the third (R820Q) is likely to be entirely solvent exposed and thus more likely to have its impact through its interactions within the sarcomere. Each of the mutations is associated with distinct disease phenotypes, with respect to severity, stage of onset, and end phase. The results are discussed in terms of understanding key structural features of these domains essential for healthy function and the role they may play in disease development.
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