ABNORMAL MYOSIN IN-VITRO MOTILITY ACTIVITY IN HYPERTROPHIC CARDIOMYOPATHY

肥厚型心肌病肌球蛋白体外运动活性异常

• 批准号: 3843405
• 负责人: L FANANAPAZIR
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3843405
• 关键词: actins; bone; congenital heart disorder; enzyme activity; enzyme mechanism; family genetics; gene expression; gene mutation; human tissue; hypertrophic myocardiopathy; linkage mapping; muscle proteins; myosins; protein structure function; striated muscles

Hypertrophic cardiomyopathy is the most common inherited heart disease and is the most important cause of sudden death in the young. Recently, a gene which controls the production of the main protein of the heart, beta myosin heavy chain gene, located on chromosome 14, has been linked to the disease in some kindreds with hypertrophic cardiomyopathy, We have found distinct mutations in the beta myosin heavy chain gene in several kindreds with hypertrophic cardiomyopathy. We have also shown that although the disease affects the heart predominantly, the cardiac protein is also expressed in skeletal tissue and that the mutant RNA and protein are also to be found in skeletal muscle. This has led us to determine whether the mutant protein in skeletal muscle has demonstrably abnormal function. The in-vitro motility assay measures the velocity of fluorescently-labelled actin filaments as they slide along myosin molecules bound to nitrocellulose-coated surface, allowing analysis of the enzymatic-mechano activity of the beta myosin. The motility activity of myosin from skeletal sample from patients with two distinct mutations were significantly less than control subjects. Thus, for the first time distinct mutations in the beta myosin heavy chain gene have been shown to result in skeletal protein with abnormal function.

肥厚型心肌病是最常见的遗传性心脏病， 是年轻人猝死的最重要原因。最近，一个基因 它控制着心脏主要蛋白质β的产生 位于14号染色体上的肌球蛋白重链基因，已经与 我们发现， 几种激酶中β肌球蛋白重链基因的不同突变 患有肥厚型心肌病 我们还表明，尽管 疾病主要影响心脏，心脏蛋白也 在骨骼组织中表达，并且突变的RNA和蛋白质也 在骨骼肌中发现。 这使我们能够确定 骨骼肌中的突变蛋白具有明显异常的功能。 的 体外运动性测定测量荧光标记的 当肌动蛋白丝沿着肌球蛋白分子滑动时， 硝化纤维素涂层的表面，允许分析的酶-机械 β-myosin的活性。 肌球蛋白的运动活性 来自具有两种不同突变患者的骨骼样品被 明显低于对照组。 因此，第一次 β肌球蛋白重链基因中的不同突变已被证明 导致骨骼蛋白功能异常。