CARNITINE TRANSPORTER IN HUMAN DISEASE

描述(改编自申请人的摘要)：(摘自申请表 摘要)原发肉碱缺乏症是一种常染色体隐性遗传病 由肉碱转运缺陷引起。肉碱对脂肪酸是必不可少的。 氧化及其缺乏会导致低酮性低血糖、骨骼和 可通过饮食肉碱预防的心脏肌病。有机阳离子 核苷结合位点转运蛋白(OCTN2)是一种高亲和力的肉碱 根据其与OCTN1的同源性克隆的转运蛋白(不包括 运输肉碱)。它在肉碱缺乏中的作用被证实 早期白血病患者OCTN2基因无义突变的鉴定 表现为原发性肉碱缺乏症。首席调查员 建议检验有原发肉碱缺乏症的家庭 在有机阳离子转运蛋白OCTN2中有一系列突变， 由这些因素引起的转运体功能损害的程度 突变与临床表现的严重程度相关。为了测试 在这一假设下，将追求以下具体目标：1)识别 原发肉碱缺乏家系中OCTN2基因突变的研究。 2)中国人错义突变在这些患者中的表达 仓鼠卵巢(CHO)细胞的致病作用和特性 它们对肉碱运输的影响。将在以下各项之间建立关联 先证者的表型和残留的肉碱转运蛋白活性 相对的突变体。3)肉碱相关的OCTN2结构域的定义 通过评估肉碱在嵌合体中的转运识别和转移 转运蛋白，通过在OCTNI的同源部分之间交换结构域而创建 和OCTN 2。4)关键区域定点突变的构建 肉碱转运蛋白OCTN_2及其对肉碱作用的测定 运输。这项研究将表征与原发疾病有关的突变 肉碱缺乏症与阐明一类新膜的功能 其改变可能导致其他类型的人类疾病的转运体。

DESCRIPTION (Adapted from applicant's abstract): (From the application abstract) Primary carnitine deficiency is an autosomal recessive disorder caused by defective carnitine transport. Carnitine is essential for fatty acid oxidation, and its deficiency results in hypoketotic hypoglycemia, skeletal and heart myopathy which are preventable by dietary carnitine. The Organic Cation Transporter with Nucleoside binding site (OCTN2) is a high-affinity carnitine transporter, which was cloned based on its homology with OCTN1 (which does not transport carnitine). Its role in carnitine deficiency was confirmed by the identification of nonsense mutations in OCTN2 in patients with early presentation of primary carnitine deficiency. The principal investigator proposes to test the hypothesis that families with primary carnitine deficiency have a spectrum of mutations in the organic cation transporter OCTN2, and that the degree of functional impairment of the transporter caused by these mutations correlates with the severity of the clinical presentation. To test this hypothesis, the following specific aims will be pursued: 1) Identification of mutations in the OCTN2 gene in families with primary carnitine deficiency. 2) Expression of missense mutations identified in these patients in Chinese Hamster Ovary (CHO) cells to confirm their causative role and to characterize their effect on carnitine transport. A correlation will be established between phenotype of the proband and residual carnitine transporter activity of the relative mutant. 3) Definition of domains of OCTN2 involved in carnitine recognition and transfer by evaluating carnitine transport in chimeric transporters, created by swapping domains between homologous portions of OCTNI and OCTN2. 4) Construction of site-directed mutations in critical domains of the OCTN2 carnitine transporter and determination of their effect on carnitine transport. This research will characterize mutations responsible for primary carnitine deficiency and clarify the function of a new class of membrane transporters whose alteration may cause other types of human diseases.