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 language | English (US) |
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Pages (from-to) | 325-333 |
Number of pages | 9 |
Journal | Circulation: Heart Failure |
Volume | 2 |
Issue number | 4 |
DOIs | |
State | Published - Jul 2009 |
Keywords
- Cardiomyopathy
- Genetics
- Hypertrophy
- Protein
- Tissue
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine