title: Clinically Linked Mutations in the Central Domains of Cardiac Myosin-Binding Protein C with Distinct Phenotypes Show Differential Structural Effects.
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.
authors.affiliation: School of Molecular Bioscience, The University of Sydney, NSW 2006, Australia.
authors.forename: Naveed Ahmed
authors.initials: NA
authors.lastname: Nadvi
authors.affiliation: School of Molecular Bioscience, The University of Sydney, NSW 2006, Australia.
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Michie
authors.affiliation: School of Molecular Bioscience, The University of Sydney, NSW 2006, Australia.
authors.forename: Ann H
authors.initials: AH
authors.lastname: Kwan
authors.affiliation: School of Molecular Bioscience, The University of Sydney, NSW 2006, Australia.
authors.forename: J Mitchell
authors.initials: JM
authors.lastname: Guss
authors.affiliation: School of Molecular Bioscience, The University of Sydney, NSW 2006, Australia. Electronic address: jill.trewhella@sydney.edu.au.
authors.forename: Jill
authors.initials: J
authors.lastname: Trewhella
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C