Molecular Mechanism of Barth Syndrome

描述（由申请人提供）：Barth综合征是一种遗传性心肌病，也会影响骨骼肌、生长和中性粒细胞。突变基因（tafazzin）同源于一个保守的磷脂酰基转移酶家族。Barth综合征患儿线粒体磷脂心磷脂缺乏，提示该疾病的主要缺陷可能确实存在于磷脂代谢中，并可能特异性影响线粒体磷脂。我们想研究他法津突变引起心肌病和骨骼肌疾病的机制。首先，我们要确定他法嗪的酶功能。我们将确定他法嗪的细胞内定位，它对脂质组成的影响，以及它的作用机制。其次，我们想研究他法嗪对线粒体结构和功能的影响。由于线粒体功能障碍可能是心肌病和骨骼肌无力的病因，我们将分析他法津缺失细胞系的线粒体超微结构和氧化磷酸化。第三，我们想要探索在我们实验室创建的Barth综合征的果蝇模型。我们将研究tafazzin缺失果蝇的脂质代谢、肌肉生理、形态学和线粒体超微结构。果蝇模型也将用于心脏研究，因为果蝇含有一个可收缩的液体泵送器官，与包括人类在内的所有心脏形成生物共享心脏发生的保守特征。该项目将深入了解一种独特疾病的病理机制，提出了一条从脂质缺陷到心-骨骼肌病的新途径。这些信息可能有助于开发治疗心肌病和骨骼肌疾病的新方法。

DESCRIPTION (provided by applicant): Barth syndrome is a hereditary cardiomyopathy that also affects skeletal muscles, growth, and neutrophils. The mutated gene (tafazzin) is homologous to a conserved family of phospholipid acyltransferases. Children with Barth syndrome are deficient in the mitochondrial phospholipid cardiolipin, suggesting that the primary defect of the disease may indeed be found in phospholipid metabolism and may specifically affect the phospholipids of mitochondria. We want to study the mechanism by which tafazzin mutation causes cardiomyopathy and skeletal muscle disease. First, we want to identify the enzymatic function of tafazzin. We will identify the intracellular localization of tafazzin, its impact on lipid composition, and its mechanism of action. Second, we want to examine the effect of tafazzin on structure and function of mitochondria. Since mitochondrial dysfunction is a plausible etiology of cardiomyopathy and skeletal muscle weakness, we will analyze mitochondrial ultrastructure and oxidative phosphorylation in cell lines with tafazzin deletion. Third, we want to explore a Drosophila model of Barth syndrome, which was created in our laboratory. We will study lipid metabolism, muscle physiology, morphology, and mitochondrial ultrastructure in fruit flies with tafazzin deletion. The Drosophila model will also be used for cardiac studies since flies contain a contractile fluid pumping organ that shares conserved features of cardiogenesis with all heart-forming creatures, including humans. The project will provide insight into the pathologic mechanism of a unique disease, which presents a novel pathway from lipid defect(s) to cardio-skeletal myopathy. Such information may be useful for the development of new therapeutic approaches to cardiomyopathy and skeletal muscle disease.