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(Circulation Research. 2009;105:219.)
© 2009 American Heart Association, Inc.

Reports

Evidence From Human Myectomy Samples That MYBPC3 Mutations Cause Hypertrophic Cardiomyopathy Through Haploinsufficiency^*

Steven Marston, O‘Neal Copeland, Adam Jacques, Karen Livesey, Victor Tsang, William J. McKenna, Shapour Jalilzadeh, Sebastian Carballo, Charles Redwood, Hugh Watkins

From Cardiovascular Science (S.M., O.C., A.J.), National Heart and Lung Institute, Imperial College London; Department of Clinical Genetics (K.L.), Churchill Hospital, Oxford; Institute of Cardiovascular Science (V.T., W.J.M.), University College, London; Department of Cardiovascular Medicine (S.J., S.C., C.R., H.W.), University of Oxford, UK.

Correspondence to Prof Hugh Watkins, Department of Cardiovascular Medicine, University of Oxford, Level 6 West Wing, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. E-mail hugh.watkins{at}cardiov.ox.ac.uk

Abstract

Rationale: Most sarcomere gene mutations that cause hypertrophic cardiomyopathy are missense alleles that encode dominant negative proteins. The potential exceptions are mutations in the MYBPC3 gene (encoding cardiac myosin-binding protein-C [MyBP-C]), which frequently encode truncated proteins.

Objective: We sought to determine whether there was evidence of haploinsufficiency in hypertrophic cardiomyopathy caused by MYBPC3 mutations by comparing left ventricular muscle from patients undergoing surgical myectomy with samples from donor hearts.

Methods and Results: MyBP-C protein and mRNA levels were quantitated using immunoblotting and RT-PCR. Nine of 37 myectomy samples had mutations in MYBPC3: 2 missense alleles (Glu258Lys, Arg502Trp) and 7 premature terminations. No specific truncated MyBP-C peptides were detected in whole muscle homogenates of hypertrophic cardiomyopathy tissue. However, the overall level of MyBP-C in myofibrils was significantly reduced (P<0.0005) in tissue containing either a truncation or missense MYBPC3 mutation: 0.76±0.03 compared with 1.00±0.05 in donor and 1.01±0.06 in non-MYBPC3 mutant myectomies.

Conclusions: The absence of any detectable truncated MyBP-C argues against its incorporation in the myofiber and any dominant negative effect. In contrast, the lowered relative level of full length protein in both truncation and missense MYBPC3 mutations argues strongly that haploinsufficiency is sufficient to cause the disease.

Key Words: cardiomyopathy • mutation • myocardial contractility

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