Mutations in sarcomeric proteins such as myosin heavy chain (MyHC) can cause either skeletal or cardiomyopathy. Over 150 mutations in the P MyHC motor domain have been found to cause hypertrophic cardiomyopathy (HCM) while 2 such mutations cause dilated cardiomyopathy (DCM). Despite the expression of p MyHC in both human heart and skeletal muscle, these individuals have little or no skeletal myopathy. Because of the large number of MyHC mutations in the motor domain, the prevailing theory is that HCM caused by MyHC mutations is the result of impaired motor function. However, disease-causing mutations in the rod domain of p MyHC that cause skeletal or cardiomyopathy have recently been discovered and these likely indicate a novel mechanism of pathogenesis. These observations lead to our proposal: to discover how 3 MyHC rod mutations lead to skeletal and cardiomyopathy and how mutations in a protein expressed in both tissues (P MyHC) can cause disease only in skeletal muscle or only in cardiac muscle. The major function of the myosin rod is to mediate the assembly of myosin into the thick filament via its C-terminal third (light meromyosin or LMM). However, the mechanisms and sequence determinants of interaction of MyHC molecules to form the highly ordered thick filament remain obscure. This is due in large part to the absence of methods for isolating and characterizing assembly intermediates and their reaction. We have developed such methods and plan to study the assembly of wild type (WT) and mutant LMMs. We believe that the analysis of these disease causing mutants will be very informative also in defining the mechanisms of myosin filament assembly. To address the tissue specificity of these myopathy mutations, we also propose to test the effects of these mutations on their interactions with tissue-specific myosin binding proteins (MyBPs). We propose to test following hypotheses: Hypothesis I: Myosin rod mutations leading to myopathy impair assembly of the thick filament. Hypothesis II: These dominant mutations will have structural consequences on the sarcomere. Hypothesis III: Myosin rod mutations will impair cardiac myocyte contractility. Hypothesis IV: Mice expressing myosin rod mutations will serve as models for skeletal and cardiomyopathy. Relevance to public health: Genetic heart disease is an important health problem and this specific type of heart disease we study is the leading cause of sudden death in young people.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Liang, Isabella Y
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Buvoli, Massimo; Buvoli, Ada; Leinwand, Leslie A (2012) Effects of pathogenic proline mutations on myosin assembly. J Mol Biol 415:807-18
Armel, Thomas Z; Leinwand, Leslie A (2010) A mutation in the beta-myosin rod associated with hypertrophic cardiomyopathy has an unexpected molecular phenotype. Biochem Biophys Res Commun 391:352-6
Armel, Thomas Z; Leinwand, Leslie A (2010) Mutations at the same amino acid in myosin that cause either skeletal or cardiac myopathy have distinct molecular phenotypes. J Mol Cell Cardiol 48:1007-13
Armel, Thomas Z; Leinwand, Leslie A (2009) Mutations in the beta-myosin rod cause myosin storage myopathy via multiple mechanisms. Proc Natl Acad Sci U S A 106:6291-6
Buvoli, Massimo; Hamady, Micah; Leinwand, Leslie A et al. (2008) Bioinformatics assessment of beta-myosin mutations reveals myosin's high sensitivity to mutations. Trends Cardiovasc Med 18:141-9