Mechanisms of myopathy caused by mutations in the myosin rod

描述（由申请人提供）：肌节蛋白（如肌球蛋白重链（MyHC））突变可导致骨骼肌或心肌病。已经发现超过150个P MyHC运动结构域突变导致肥厚型心肌病（HCM），而2个这样的突变导致扩张型心肌病（DCM）。尽管在人类心脏和骨骼肌中表达p MyHC，但这些个体很少或没有骨骼肌病变。由于在运动域中存在大量的MyHC突变，流行的理论是由MyHC突变引起的HCM是运动功能受损的结果。然而，最近发现了导致骨骼肌或心肌病的pMyHC杆结构域中的致病突变，这些可能表明了一种新的发病机制。这些观察导致我们的建议：发现3个MyHC杆突变如何导致骨骼肌和心肌病，以及在两种组织中表达的蛋白质（P MyHC）突变如何仅在骨骼肌或仅在心肌中引起疾病。肌球蛋白杆的主要功能是介导肌球蛋白通过其C-末端第三部分（轻解肌球蛋白或LMM）组装成粗肌丝。然而，MyHC分子相互作用形成高度有序的粗丝的机制和序列决定因素仍然不清楚。这在很大程度上是由于缺乏用于分离和表征组装中间体及其反应的方法。我们已经开发了这样的方法，并计划研究野生型（WT）和突变型LIGHT 3的组装。我们相信，这些致病突变体的分析将是非常有益的，也在确定肌球蛋白丝组装的机制。为了解决这些肌病突变的组织特异性，我们还建议测试这些突变对它们与组织特异性肌球蛋白结合蛋白（MyBPs）相互作用的影响。我们建议测试以下假设：假设一：肌球蛋白杆突变导致肌病损害大会的粗丝。假设二：这些显性突变将对肌节产生结构性影响。假设三：肌球蛋白杆突变将损害心肌细胞收缩力。假设四：表达肌球蛋白杆突变的小鼠将作为骨骼肌和心肌病的模型。与公共卫生的相关性：遗传性心脏病是一个重要的健康问题，我们研究的这种特殊类型的心脏病是年轻人猝死的主要原因。

DESCRIPTION (provided by applicant): 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.