FHC Tn Mutations: Functional Consequences & Mechanisms

家族性肥厚型心肌病(FHC)是一种常染色体显性遗传病，几乎与所有主要心肌肌节蛋白的突变有关。一般而言，肌球蛋白重链(MHC)突变的个体心肌肥厚程度较高，而具有心肌肌钙蛋白T(CTnT)和部分已报道的肌钙蛋白I(CTnI)突变的个体心肌肥厚较少，而心脏性猝死(SCD)的发生率较高。最近，据报道，肌钙蛋白C的一个单一突变可能与FHC有关。尽管几种突变在体外已经被广泛描述，但它们是如何导致心肌肥厚或SCD的仍不清楚。我们的工作假设是，FHC肌钙蛋白突变改变了PCA-力和-ATPase关系、肌肉发展最大力和ATPase活性的能力、肌球蛋白跨桥动力学、收缩效率以及肌肉做功的能力。这种增加钙敏感性的突变与猝死的关系更密切，而降低肌肉力量形成能力的突变与肥大关系更密切。最近报道的转基因小鼠结果以及我们从三个表达人cTnT(HCTnT)FHC突变(I79N、F1101和R278C)和HCTnI-R145G的转基因小鼠株系的数据支持这一假设。这项建议的目的是全面研究体外后果(例如，收缩的钙敏感性，力量发展/松弛的动力学，受损的cTnI抑制功能等)。对现有和新的转基因小鼠中不同的FHC相关肌钙蛋白突变进行研究，以确定FHC发病的关键机制。这项应用汇集了迈阿密大学具有不同背景的才华横溢的科学家，代表了研究这些肌钙蛋白突变的全面方法。我们的目标是在我们的动物模型中观察到cTnT、cTnI和cTNC突变对心肌收缩的钙调节的影响，并与人类FHC的发病机制相关，特别是在已有报道的心脏性猝死病例中。这些研究将在相同的实验条件下确定不同的肌钙蛋白T、肌钙蛋白I和肌钙蛋白C突变的功能后果，从而有助于确定肌钙蛋白连锁的FHC的发病机制(S)，并导致潜在的治疗策略

Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disease, which has been associated with mutations in almost every major cardiac sarcomeric protein. Whereas individuals with myosin heavy chain (MHC) mutations, in general, have a higher level of cardiac hypertrophy, those with cardiac Troponin T (CTnT) and some of the reported Troponin I (CTnI) mutations have less hypertrophy and a higher incidence of sudden cardiac death (SCD). Most recently, a single mutation in Troponin C has been reported to be possibly associated with FHC. Although several mutations have been extensively characterized in vitro, it is still unclear how they cause cardiac hypertrophy or SCD. Our working hypothesis is that FHC troponin mutations alter the pCa-force and -ATPase relationships, the ability of the muscle to develop maximum force and ATPase activity, myosin cross-bridge kinetics, efficiency of contraction, and the ability of the muscle to do work. That mutations, which increase Ca2+- sensitivity, are more closely associated with sudden death, while mutations, which decrease the ability of the muscle to develop force, are more closely associated with hypertrophy. Recently reported transgenic mouse results along with our data from three transgenic mouse lines expressing the human CTnT (HCTnT) FHC mutations (I79N, F1101 and R278C) and HCTnI-R145G, support this hypothesis. The objective of this proposal is to comprehensively study the in vitro consequences (e.g. Ca2+-sensitivity of contraction, kinetics of force development/relaxation, impaired CTnI inhibitory function, etc.) of different FHC associated Troponin mutations in existing and new transgenic mice to identify the key mechanisms involved in the pathogenesis of FHC. This application brings together highly talented scientists at the University of Miami with varied backgrounds and represents a comprehensive approach to the study of these troponin mutations. Our goal is to correlate, the observed effects of mutations in CTnT, CTnI and CTnC on the Ca2+ regulation of cardiac muscle contraction in our animal models, with the pathogenesis of FHC in humans, especially in cases where sudden cardiac deaths have been reported. These studies will determine the functional consequences of different troponin T, troponin I and troponin C mutations under the same experimental conditions, and thus help identify key mechanism(s) involved in the pathogenesis of Troponin-linked FHC and lead to potential therapeutic strategies