Published Online
on May 13, 2009

A more recent version of this article appeared on July 1, 2009

This Article Full Text (PDF) All Versions of this Article: 2/4/325    most recent CIRCHEARTFAILURE.108.789735v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Theis, J. L. Articles by Ackerman, M. J. Search for Related Content PubMed PubMed Citation Articles by Theis, J. L. Articles by Ackerman, M. J. Related Collections Clinical genetics Gene expression Hypertrophy Myocardial cardiomyopathy disease

Original Article

Expression Patterns of Cardiac Myofilament Proteins - Genomic and Protein Analysis of Surgical Myectomy Tissue from Patients with Obstructive Hypertrophic Cardiomyopathy

Jeanne L. Theis¹; Johan Martijn Bos¹; Jason D. Theis¹; Dylan V. Miller¹; Joseph A. Dearani¹; Hartzell V. Schaff¹; Bernard J. Gersh¹; Steve R. Ommen¹; Richard L. Moss² and Michael J. Ackerman^1,3

¹ Mayo Clinic, Rochester, MN;
² University of Wisconsin, Madison, WI

³ E-mail: ackerman.michael{at}mayo.edu

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 blot with localization graded from immunohistochemical staining of tissue sections. Overall, 25/47 (53%) patients had myofilament-HCM including 12 with MYBPC3-HCM and 9 with MYH7-HCM. Compared to 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 to 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.

Key Words: cardiomyopathy • genetics • hypertrophy • proteins • tissue