THE CARNITINE TRANSPORTER IN HUMAN DISEASE

描述（由申请人提供）：本项目的目的是描述肉碱转运蛋白在人类疾病中的作用。肉碱将长链脂肪酸转移到线粒体膜上进行随后的β氧化。高亲和OCTN2肉毒碱转运蛋白缺陷导致原发性肉毒碱缺乏，表现为低酮性低血糖和/或骨骼肌/心肌病。随着肉毒碱转运仅部分受损的患者和肉毒碱转运基因2个突变完全无症状的成年患者（24-37岁）的肉毒碱缺乏症症状的发现，这种表型现已扩大。我们假设这种表型变异可能是由于不寻常的OCTN2突变，其他肉毒碱转运蛋白的贡献，或其他基因编码蛋白质与OCTN2相互作用或参与脂肪酸氧化的影响。为了验证这一假设，我们将定义异常OCTN2突变对功能的影响，评估其他肉毒碱转运蛋白的活性和序列，定义与OCTN2肉毒碱转运蛋白相互作用的蛋白质，并在异常形式的肉毒碱缺乏症患者中寻找其基因的改变。具体目标如下：目标1。研究异常表型肉毒碱缺乏症患者的OCTN2肉毒碱转运蛋白突变。我们将排除可能的显性负性突变、与其他脂肪酸氧化基因突变的协同杂合性以及其他肉毒碱转运蛋白的变异。目标2。利用2-杂交系统鉴定与肉毒碱转运体OCTN2相互作用的蛋白质。将在部分肉毒碱缺乏症和肉毒碱转运体基因无突变的症状性患者中寻找所鉴定的基因突变。本研究将扩大肉碱缺乏症的表型，阐明不同寻常形式的肉碱缺乏症的分子基础，确定细胞内蛋白网络在膜转运蛋白功能中的重要性，并确定少量肉碱转运蛋白在人类疾病中的可能作用。

DESCRIPTION (provided by applicant): The objective of this project is to characterize the role of carnitine transporters in human disease. Carnitine transfers long-chain fatty acids across the mitochondrial membrane for subsequent beta oxidation. A defect in the high-affinity OCTN2 carnitine transporter causes primary carnitine deficiency characterized by hypoketotic hypoglycemia and/or skeletal/cardiac myopathy. This phenotype has now expanded with the identification of symptoms of carnitine deficiency in patients with only partially impaired carnitine transport and adult patients (age 24-37) with 2 mutations in the carnitine transporter gene completely asymptomatic. We hypothesize that this phenotypic variability can be due to unusual OCTN2 mutations, to the contribution of other carnitine transporters, or to the effect of other genes encoding proteins interacting with OCTN2 or involved in fatty acid oxidation. To test this hypothesis, we will define the effect on function of unusual OCTN2 mutations, evaluate activity and sequence of other carnitine transporters, define proteins interacting with the OCTN2 carnitine transporter and look for alterations in their genes in patients with unusual forms of carnitine deficiency. The following specific aims will be accomplished: Aim 1. Study mutations in the OCTN2 carnitine transporter of patients with unusual phenotype of carnitine deficiency. We will exclude a possible dominant-negative effect of the mutation identified, synergistic heterozygosity with mutations in other fatty acid oxidation genes and variations in other carnitine transporters. Aim 2. Identification of proteins interacting with the carnitine transporter OCTN2 using the 2-hybrid system. Mutations in the genes identified will be sought in symptomatic patients with partial carnitine deficiency and no mutations in the carnitine transporter gene. This study will expand the phenotype of carnitine deficiency, clarify the molecular basis of unusual forms of carnitine deficiency, define the importance of intracellular protein networks in the functioning of membrane transporters, and identify the possible role of minor carnitine transporters in human disease.