Expression patterns of cardiac myofilament proteins: genomic and protein analysis of surgical myectomy tissue from patients with obstructive hypertrophic cardiomyopathy.

Abstract

BACKGROUND:

Mutations in myofilament proteins, most commonly MYBPC3-encoded myosin-binding protein C and MYH7-encoded beta-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.

• Authors: 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 J Ackerman
• Journal: Circulation. Heart failure (Circ Heart Fail) Vol. 2 Issue 4 Pg. 325-33 (Jul 2009) ISSN: 1941-3297 [Electronic] United States
• PMID: 19808356 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• MYH7 protein, human
• myosin-binding protein C
• Cardiac Myosins
• Myosin Heavy Chains

Topics

• Actin Cytoskeleton (genetics)
• Adolescent
• Adult
• Cardiac Myosins (genetics)
• Cardiomyopathy, Hypertrophic (genetics)
• Carrier Proteins (genetics)
• DNA Mutational Analysis
• Female
• Gene Expression
• Humans
• Male
• Middle Aged
• Mutation (genetics)
• Myosin Heavy Chains (genetics)