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中国人2型糖尿病合并高甘油三酯血症患者脂蛋白酯酶基因突变及功能分析
作者姓名:Yang T  Lam CW  Tsang MW  Chan LY  Poon PM  Huang SZ  Pang CP
作者单位:1. Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College
2. 香港中文大学,化学病理学系
3. United Christian Hospital, Hong Kong
4. Department of Ophthalmology &Visual Sciences, the Chinese University of Hong Kong
基金项目:香港中文大学(2040585和2040661),香港研究资助局(4282/98M)资助
摘    要:目的 研究中国人2型糖尿病合并高甘油三酯血症患者脂蛋白醒酶(1ipoprotein lipase,LPL)基因突变及对酶功能的影响,从脂代谢途径探讨引发糖尿病的遗传因素。方法 对高甘油三酯及血脂正常的2型糖尿病患者和正常人的LPL基因进行研究。利用PCR—SSCP、PCR—RFLP及DNA测序技术对LPL基因的启动子和10个外显子区域进行突变检测,针对特异位点进行体外定点突变和酶活力表达研究,利用网上工具平台Swiss-PDB Viewer对正常和突变蛋白进行二级结构模拟分析。结果 在177例高甘油三酯2型糖尿病患者中检测到4种错义突变:Ala71Thr、Val181IIe、Glyl88Glu和Glu242Lys,在正常血脂的糖尿病患者和健康人组中没有检出以上突变。这4种突变位于进化上高度保守的氨基酸位点,并分别在高度保守的外显子3、5及6区域。体内和体外酶活力研究表明,这4个突变均引起了酶活力降低甚至失活,其改变程度可以从它们所在序列的保守性、在酶功能结构城中的相对位置、相应的二级结构改变和氨基酸特性获得解释。结论 在受累个体中,LPL突变是引起患者血浆甘油三酯升高的直接原因,是其发展成2型糖尿病的遗传性易感因素。

关 键 词:2型糖尿病  脂蛋白酯酶  高甘油三酯血症  突变
修稿时间:2002年11月15

Mutation-function analysis in the lipoprotein lipase gene of Chinese patients with hypertriglyceridemic type 2 diabetes
Yang T,Lam CW,Tsang MW,Chan LY,Poon PM,Huang SZ,Pang CP.Mutation-function analysis in the lipoprotein lipase gene of Chinese patients with hypertriglyceridemic type 2 diabetes[J].Acta Academiae Medicinae Sinicae,2003,25(2):134-141.
Authors:Yang Tao  Lam Ching-wan  Tsang Man-wo  Chan Lisa Y S  Poon Priscilla M K  Huang Shang-zhi  Pang Chi-pui
Institution:Department of Chemical Pathology, Chinese University of Hong Kong, Hong Kong, China. yangtao2k@hotmail.com
Abstract:Objective To investigate the role of lipoprotein lipase (LPL) gene on Chinese patients with hypertriglyceridemic type 2 diabetes. Methods Three subject groups, including hypertriglyceridemic group, normalipidemic type 2 diabetes group and healthy controls, were recruited and screened for sequence changes in LPL gene with PCR, SSCP, restriction analysis and direct DNA sequencing. LPL mass and activity in post-heparin plasma and in in vitro expression were investigated. Comparative modeling was performed via Swiss-PDB Viewer to provide the potential 2-D structures of wildtype and mutant proteins. Results Four missense mutations, Ala71Thr, Vall81Ile, Gly188Glu and Glu242Lys, were identified in patients with hypertriglyceridemic type 2 diabetes, and not in both normalipidemic diabetes and the control subjects. The four missense mutations were located in the highly conserved amino acid sites, which are involved in highly conserved exon 3, 5, or 6 regions. They led to reduced LPL mass and enzyme activities in both post-heparin plasma and in vitro expression. The modeled structures displayed the differences to a great extent between the mutant and widetype molecules. Conclusion These results indicated that the 4 missense mutations lead to LPL deficiency and subsequent hypertriglyceridemia. The LPL deficiency predispose a progressive diabetic pathway to those affected individuals. LPL gene is one of susceptibility gene for hypertriglyceridemic type 2 diabetes.
Keywords:type 2 diabetes  lipoprotein lipase  hypertriglyeeridemia  mutation
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