THE CARNITINE TRANSPORTER IN HUMAN DISEASE

描述（由申请人提供）：本项目的目的是表征肉毒碱转运蛋白在人类疾病中的作用。肉毒碱转移长链脂肪酸穿过线粒体膜，用于随后的β氧化。高亲和力OCTN 2肉毒碱转运蛋白的缺陷导致原发性肉毒碱缺乏，其特征为低酮性低血糖和/或骨骼/心肌病。这种表型现在已经扩大，在只有部分受损的肉毒碱转运和成人患者（24-37岁）与肉毒碱转运基因完全无症状的2个突变的肉毒碱缺乏症的症状的鉴定。我们假设这种表型变异可能是由于不寻常的OCTN 2突变，其他肉毒碱转运蛋白的贡献，或其他基因编码的蛋白质与OCTN 2相互作用或参与脂肪酸氧化的影响。为了验证这一假设，我们将定义不寻常的OCTN 2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OCTN 2肉毒碱转运蛋白相互作用的蛋白质，并在具有不寻常形式的肉毒碱缺乏症的患者中寻找其基因的改变。将实现以下具体目标：目标1。研究具有不寻常的肉毒碱缺乏表型的患者的OCTN 2肉毒碱转运蛋白的突变。我们将排除一个可能的显性负效应的突变，协同杂合性与其他脂肪酸氧化基因的突变和其他肉毒碱转运蛋白的变化。目标2.使用双杂交系统鉴定与肉毒碱转运蛋白OCTN 2相互作用的蛋白质。将在部分肉毒碱缺乏症和肉毒碱转运蛋白基因无突变的有症状患者中寻找所鉴定的基因突变。这项研究将扩大肉毒碱缺乏症的表型，澄清不寻常形式的肉毒碱缺乏症的分子基础，确定细胞内蛋白质网络在膜转运蛋白功能的重要性，并确定在人类疾病中的可能作用的次要肉毒碱转运蛋白。

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.