Expression patterns of cardiac myofilament proteins

Jeanne L. Theis, J. Martijn Bos, Jason D. Theis, Dylan V. Miller, Joseph A. Dearani, Hartzell V Schaff, Bernard J. Gersh, Steve R. Ommen, Richard L. Moss, Michael John Ackerman

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background-Mutations in myofilament proteins, most commonly MYBPC3-encoded myosin-binding protein C and MYH7-encoded ß-myosin heavy chain, can cause hypertrophic cardiomyopathy (HCM). Despite significant advances in structure-function relationships pertaining to the cardiac sarcomere, there is limited knowledge of how a mutation leads to clinical HCM. We, therefore, set out to study expression and localization of myofilament proteins in left ventricular tissue of patients with HCM. Methods and Results-Frozen surgical myectomy specimens from 47 patients with HCM were examined and genotyped for mutations involving 8 myofilament-encoding genes. Myofilament protein levels were quantified by Western blotting with localization graded from immunohistochemical staining of tissue sections. Overall, 25 of 47 (53%) patients had myofilament-HCM, including 12 with MYBPC3-HCM and 9 with MYH7-HCM. As compared with healthy heart tissue, levels of myofilament proteins were increased in patients manifesting a mutation in either gene. Patients with a frameshift mutation predicted to truncate MYBPC3 exhibited marked disturbances in protein localization as compared with missense mutations in either MYBPC3 or MYH7. Conclusions-In this first expression study in human HCM tissue, increased myofilament protein levels in patients with either MYBPC3-or MYH7-mediated HCM suggest a poison peptide mechanism. Specifically, the mechanism of dysfunction may vary according to the genetic subgroup suggested by a distinctly abnormal distribution of myofilament proteins in patients manifesting a truncation mutation in MYBPC3.

Original languageEnglish (US)
Pages (from-to)325-333
Number of pages9
JournalCirculation: Heart Failure
Volume2
Issue number4
DOIs
StatePublished - Jul 2009

Fingerprint

Myofibrils
Hypertrophic Cardiomyopathy
Proteins
Mutation
Sarcomeres
Frameshift Mutation
Myosin Heavy Chains
Poisons
Missense Mutation
Genes
Western Blotting
Staining and Labeling
Peptides

Keywords

  • Cardiomyopathy
  • Genetics
  • Hypertrophy
  • Protein
  • Tissue

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Expression patterns of cardiac myofilament proteins. / Theis, Jeanne L.; Bos, J. Martijn; Theis, Jason D.; Miller, Dylan V.; Dearani, Joseph A.; Schaff, Hartzell V; Gersh, Bernard J.; Ommen, Steve R.; Moss, Richard L.; Ackerman, Michael John.

In: Circulation: Heart Failure, Vol. 2, No. 4, 07.2009, p. 325-333.

Research output: Contribution to journalArticle

Theis, JL, Bos, JM, Theis, JD, Miller, DV, Dearani, JA, Schaff, HV, Gersh, BJ, Ommen, SR, Moss, RL & Ackerman, MJ 2009, 'Expression patterns of cardiac myofilament proteins', Circulation: Heart Failure, vol. 2, no. 4, pp. 325-333. https://doi.org/10.1161/CIRCHEARTFAILURE.108.789735
Theis, Jeanne L. ; Bos, J. Martijn ; Theis, Jason D. ; Miller, Dylan V. ; Dearani, Joseph A. ; Schaff, Hartzell V ; Gersh, Bernard J. ; Ommen, Steve R. ; Moss, Richard L. ; Ackerman, Michael John. / Expression patterns of cardiac myofilament proteins. In: Circulation: Heart Failure. 2009 ; Vol. 2, No. 4. pp. 325-333.
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AB - Background-Mutations in myofilament proteins, most commonly MYBPC3-encoded myosin-binding protein C and MYH7-encoded ß-myosin heavy chain, can cause hypertrophic cardiomyopathy (HCM). Despite significant advances in structure-function relationships pertaining to the cardiac sarcomere, there is limited knowledge of how a mutation leads to clinical HCM. We, therefore, set out to study expression and localization of myofilament proteins in left ventricular tissue of patients with HCM. Methods and Results-Frozen surgical myectomy specimens from 47 patients with HCM were examined and genotyped for mutations involving 8 myofilament-encoding genes. Myofilament protein levels were quantified by Western blotting with localization graded from immunohistochemical staining of tissue sections. Overall, 25 of 47 (53%) patients had myofilament-HCM, including 12 with MYBPC3-HCM and 9 with MYH7-HCM. As compared with healthy heart tissue, levels of myofilament proteins were increased in patients manifesting a mutation in either gene. Patients with a frameshift mutation predicted to truncate MYBPC3 exhibited marked disturbances in protein localization as compared with missense mutations in either MYBPC3 or MYH7. Conclusions-In this first expression study in human HCM tissue, increased myofilament protein levels in patients with either MYBPC3-or MYH7-mediated HCM suggest a poison peptide mechanism. Specifically, the mechanism of dysfunction may vary according to the genetic subgroup suggested by a distinctly abnormal distribution of myofilament proteins in patients manifesting a truncation mutation in MYBPC3.

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