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MOLECULAR-GENETIC STUDY OF FAMILIAR HYPERLIPOPROTEINEMIA RELATED TO ATHEROSCLEROSIS

与动脉粥样硬化相关的常见高脂蛋白血症的分子遗传学研究

基本信息

批准号：
05454326
负责人：
YAMAMOTO Akira
金额：
$ 4.16万
依托单位：
NATIONAL CARDIOVASCULAR CENTER RESEARCH INSTITUTE
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454326/
关键词：
Atherosclerosis Hyperlipoproteinemia Cholesterol Triglyceride LDL-receptor Lipoprotein lipase Hepatic lipase Apolipoproteins

项目摘要

The purpose of this study is to elucidate the mechanism of hyperlipoproteinemia on the basis of molecular biology and genetics and contribute to the prevention of atherosclerotic vascular diseases.1) Analysis of the LDL-receptor gene mutation in familial hypercholesterolemia (FH) : A point mutation at the splice donor site of intron 12 was identified in 7 out of 24 FH homozygotes from independent families. This mutation was detected in 15% of the patients with heterozygous FH as the most popular mutation of LDL receptor gene among Japanese. All the three mutations with a large deletion in LDL receptor gene were found to be resulted from Alu-Alu recombination.2) Changes in apolipoproteins as a cause of or related to hypercholesterolemia : (a) We detected a case of moderate hyperlipidemia, whose LDL showed a decrease in affinity to the cell surface receptor (s). The replacement of amino acid 3500 in apolipoprotein B (apo B), which is a relatively common mutation related to hypercholester … More olemia in Europe, was not found in this mutant.The analysis of apo B gene is now under investigation.(b) In WHHL rabbit, an animal model of FH,there were marked decreases in apo A-I and A-IV,making a sharp contrast to the alimentary hyperlipedemia, in which both apo A-I and A-IV were in the nomal range. The decrease in these apolipoproteins could be an additional factor leading to the progression of atherosclerosis through the disturbance of reverse cholesterol transport.3) Deficiency in lipoprotein lipase (LPL) and hepatic lipase (HL) as a cause of hypertriglyceridemia : LPL deficiency in heterozygous state was frequently found in type IV hyperlipoproteinemia. High alcohol intake and hyperinsulinemia or glucose intolerance were the factors, which manifest hypertriglyceridema in patients with LPL deficiency. The complete deficiency in HL is rare. We found a case of this kind of disorder and identified the site of mutation in exon 2 (T*G). Peculiar characteristic on HL deficiency was the presence of TG-rich LDL together with TG-rich HDL. Less

本研究的目的是从分子生物学和遗传学的角度阐明高脂蛋白血症的发病机制，为动脉粥样硬化性血管疾病的预防提供理论依据。1）家族性高胆固醇血症（FH）患者LDL受体基因突变分析：在24例FH纯合子中，有7例发生内含子12剪接供体位点的点突变。在15%的杂合子FH患者中检测到这种突变，这是日本人中最常见的LDL受体基因突变。2）载脂蛋白的改变是高胆固醇血症的原因或与之相关：（a）我们检测到一例中度高脂血症患者，其LDL与细胞表面受体的亲和力降低。载脂蛋白B（apo B）第3500位氨基酸的替换是一种相对常见的与高胆固醇相关的突变 ...更多信息在该突变体中未发现欧洲的高脂血症，载脂蛋白B基因的分析正在进行中。(b)在FH动物模型WHHL兔中，载脂蛋白A-I和A-IV明显降低，与饮食性高脂血症形成鲜明对比，其中载脂蛋白A-I和A-IV均在正常范围内。3）脂蛋白脂酶（LPL）和肝脂酶（HL）的缺乏是高脂血症的一个原因：LPL的杂合子缺陷常见于IV型高脂血症。高饮酒、高胰岛素血症或糖耐量异常是LPL缺乏症患者高脂血症的主要表现。HL中的完全缺乏是罕见的。我们发现了一例这种疾病，并确定了第2外显子（T*G）的突变位点。HL缺乏的特殊特征是富含TG的LDL和富含TG的HDL的存在。少