title: An Investigation of the Molecular Mechanism of Double cMyBP-C Mutation in a Patient with End-Stage Hypertrophic Cardiomyopathy.
abstract: Mutations in the gene coding for cardiac myosin binding protein-C (cMyBP-C), a multi-domain (C0-C10) protein, are a major causative factor for inherited hypertrophic cardiomyopathy. Patients carrying mutations in this gene have an extremely heterogeneous clinical course, with some progressing to end-stage heart failure. The cause of this variability is unknown. We here describe molecular modeling of a double mutation in domains C1 (E258K) and C2 (E441K) in a patient with severe HCM phenotype. The three-dimensional structure for the C1-motif-C2 complex was constructed with double and single mutations being introduced. Molecular dynamic simulations were performed for 10 ns under physiological conditions. The results showed that both E258K and E441K in isolation can predominantly affect the native domain as well as the nearby motif via conformational changes and result in an additive effect when they coexist. These changes involve important regions of the motif such as phosphorylation and potential actin-binding sites. Moreover, the charge reversal mutations altered the surface electrostatic properties of the complex. In addition, we studied protein expression, which showed that the mutant proteins were expressed and we can suppose that the severe phenotype was not due to haploinsufficiency. However, additional studies on human gene expression will need to confirm this hypothesis. The double mutation affecting the regulatory N-terminal of cMyBP-C have the potential of synergistically interfering with the binding to neighbouring domains and other sarcomeric proteins. These effects may account for the severe phenotype and clinical course observed in the complex cMyBP-C genotypes.
authors.affiliation: Qatar Cardiovascular Research Centre, Qatar Foundation, Doha, Qatar.
authors.forename: Poornima
authors.initials: P
authors.lastname: Gajendrarao
authors.forename: Navaneethakrishnan
authors.initials: N
authors.lastname: Krishnamoorthy
authors.forename: Senthil
authors.initials: S
authors.lastname: Selvaraj
authors.forename: Francesca
authors.initials: F
authors.lastname: Girolami
authors.forename: Franco
authors.initials: F
authors.lastname: Cecchi
authors.forename: Iacopo
authors.initials: I
authors.lastname: Olivotto
authors.forename: Magdi
authors.initials: M
authors.lastname: Yacoub
mesh_terms: D000328:Adult; D020816:Amino Acid Motifs; D001665:Binding Sites; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004252:DNA Mutational Analysis; D018619:Echocardiography, Doppler, Pulsed; D004562:Electrocardiography; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014162:Transfection; D055815:Young Adult; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C