THE CARNITINE TRANSPORTER IN HUMAN DISEASE

人类疾病中的肉碱转运蛋白

基本信息

批准号：
7626735
负责人：
NICOLA LONGO
金额：
$ 26.25万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/7626735
关键词：
Adult Affinity Age Antibodies Cardiac Carnitine Cations Defect Disease Dominant-Negative Mutation Enzymes Genes Grant Hybrids Hypoglycemia Impairment Life Measures Membrane Transport Proteins Metabolic Diseases Minor Molecular Mutation Myopathy Nonsense Mutation Online Mendelian Inheritance In Man Patients Phenotype Precipitation Proteins Research Research Personnel Role Symptoms System Testing Variant base fatty acid oxidation human disease interest long chain fatty acid mitochondrial membrane mutant novel oxidation prevent programs protein expression skeletal trafficking yeast two hybrid system

Adult Affinity Age Antibodies Cardiac Carnitine Cations Defect Disease Dominant-Negative Mutation Enzymes Genes Grant Hybrids Hypoglycemia Impairment Life Measures Membrane Transport Proteins Metabolic Diseases Minor Molecular Mutation Myopathy Nonsense Mutation Online Mendelian Inheritance In Man Patients Phenotype Precipitation Proteins Research Research Personnel Role Symptoms System Testing Variant base fatty acid oxidation human disease interest long chain fatty acid mitochondrial membrane mutant novel oxidation prevent programs protein expression skeletal trafficking yeast two hybrid system

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项目摘要

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）：该项目的目的是表征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以进行β氧化。高亲和力OCTN2肉碱转运蛋白的缺陷导致原发性肉碱缺乏症，其特征是低血糖低血糖和/或骨骼/心脏肌病。现在，这种表型随着肉碱运输和成年患者（24-37岁）的肉碱缺乏症状的鉴定而扩展，在肉碱转运蛋白基因中完全无症状。我们假设这种表型变异性可能是由于异常的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其他基因的作用。为了检验这一假设，我们将定义对其他肉碱转运蛋白的活性和序列的影响的影响，定义与contn2肉碱转运蛋白相互作用的蛋白质，并寻找其基因中异常形式肉碱缺乏症患者的基因改变。将实现以下特定目标：目标1。研究肉碱缺乏表型的八icn2肉碱转运蛋白中的研究突变。我们将排除其他脂肪酸氧化基因中突变的突变的可能的显性阴性作用以及其他肉碱转运蛋白的变化。 AIM 2。使用2杂交系统鉴定与肉碱转运蛋白相互作用的蛋白质。鉴定基因的突变将在有症状缺乏症的有症状患者中寻求，并且在肉碱转运蛋白基因中无突变。这项研究将扩大肉碱缺乏症的表型，阐明肉碱缺乏症的异常形式的分子基础，确定细胞内蛋白网络在膜转运蛋白功能中的重要性，并确定次要肉碱转运蛋白在人类疾病中的可能作用。