An Investigation of the Molecular Mechanism of Double cMyBP-C Mutation in a Patient with End-Stage Hypertrophic Cardiomyopathy

Poornima Gajendrarao, Navaneethakrishnan Krishnamoorthy, Senthil Selvaraj, Francesca Girolami, Franco Cecchi, Iacopo Olivotto, Magdi Yacoub

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)232-243
Number of pages12
JournalJournal of Cardiovascular Translational Research
Volume8
Issue number4
DOIs
Publication statusPublished - 20 Jun 2015

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Keywords

  • Cardiac myosin binding protein-C
  • Double mutation
  • Hypertrophic cardiomyopathy
  • Molecular dynamics simulation
  • Protein expression
  • Structure–function relationship

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics
  • Genetics(clinical)
  • Molecular Medicine
  • Pharmaceutical Science

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