THE CARNITINE TRANSPORTER IN HUMAN DISEASE

人类疾病中的肉碱转运蛋白

• 批准号: 7148256
• 负责人: NICOLA LONGO
• 金额: $ 27.58万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148256
• 关键词: CHO cells; binding sites; carnitine; clinical research; confocal scanning microscopy; fatty acids; gene mutation; genetic disorder; human genetic material tag; human subject; inborn metabolism disorder; membrane transport proteins; molecular pathology; oxidation; protein localization; protein protein interaction; protein structure function; site directed mutagenesis; yeast two hybrid system

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.

描述（由申请人提供）：该项目的目标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穿过线粒体膜以进行随后的β氧化。高亲和力 OCTN2 肉碱转运蛋白的缺陷会导致原发性肉碱缺乏，其特征是低酮性低血糖和/或骨骼肌/心肌病。现在，随着肉碱转运部分受损的患者和肉碱转运蛋白基因有 2 个突变但完全无症状的成年患者（24-37 岁）中肉碱缺乏症状的识别，这种表型已经扩大。我们假设这种表型变异可能是由于不寻常的 OCTN2 突变、其他肉碱转运蛋白的贡献或编码与 OCTN2 相互作用或参与脂肪酸氧化的蛋白质的其他基因的影响。为了检验这一假设，我们将定义不寻常的 OCTN2 突变对功能的影响，评估其他肉碱转运蛋白的活性和序列，定义与 OCTN2 肉碱转运蛋白相互作用的蛋白质，并在患有不寻常形式的肉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. 研究具有异常肉碱缺乏表型的患者的 OCTN2 肉碱转运蛋白突变。我们将排除所识别的突变、与其他脂肪酸氧化基因的突变和其他肉碱转运蛋白的变异的协同杂合性的可能的显性失活效应。目标 2. 使用 2-杂交系统鉴定与肉碱转运蛋白 OCTN2 相互作用的蛋白质。将在部分肉碱缺乏且肉碱转运蛋白基因无突变的有症状患者中寻找已确定的基因突变。这项研究将扩大肉碱缺乏的表型，阐明不寻常形式的肉碱缺乏的分子基础，定义细胞内蛋白质网络在膜转运蛋白功能中的重要性，并确定次要肉碱转运蛋白在人类疾病中的可能作用。