中国人群PRNP基因多态性分析及朊病毒新突变分子致病机制的初步研究

发布时间：2018-02-23 13:30

本文关键词： 人朊病毒病 PRNP基因基因多态性插入突变蛋白聚集　出处：《武汉大学》2005年博士论文　论文类型：学位论文

【摘要】：可传播性海绵状脑病(TSE)是人和动物的一类罕见的、亚急性致死性神经退化疾病,包括疯牛病、羊搔痒病和近年来出现的人新型变异克雅氏病等。TSEs由细胞型朊病毒蛋白PrP~C转变成致病型朊病毒蛋白PrP~(Sc)引起,因此也称朊病毒病。人的朊病毒病有多种,其中10—15%可以遗传,并与人的朊病毒蛋白基因PRNP的突变有关,另有85%呈散发性。散发型朊病毒病的具体发生机制尚不清楚。已有的分析证明,PRNP基因的M129V和E219K多态性与朊病毒病的易感性关系密切,而且不同种族人群的M129V和E219K基因型和等位基因频率差异很大。为了解我国PRNP基因型和等位基因频率的分布,我们调查了总计626例正常人的PRNP基因的M129V和E219K多态性,包括汉族、回族和维吾尔族三个民族的人群。我们发现129M/M纯合子基因型在三个民族中的分布明显不同,汉族129M/M基因型频率最高(98%),其次是回族(85%),最低为维吾尔族(60%),均大大高于欧洲人群的129M/M基因型频率。而219E/E的基因型频率最高的是维吾尔族(98%),其次为回族(96%)和汉族(90%)。这一结果提示我国人群可能较欧洲人群对朊病毒病更为易感。此外,我们还分析了另外两个较为少见的PRNP多态性位点:A117A和八肽重复区缺失一个八肽单位的突变(1-OPRD)。我们在3例维吾尔族个体中发现了A117A静息突变(gca→gcg);在4例回族个体(2.0%)和1例汉族个体(0.5%)中发现了杂合的1-OPRD突变。 PRNP基因序列分析是发现遗传型朊病毒病的重要途径。我们用克隆测序的方法首次发现了插入3个额外八肽拷贝(72bp)的朊病毒新突变,并将其命名为PrP8G。PrP8G八肽重复区的基因序列是R1、R2、R2、R2a、R2、R2、R3、R4,与野生型序列(R1、R2、R2、R3、R4)对照,突变序列在R2和R3之间多出了R2a、R2、R2三个八肽拷贝,测序的结果还显示这一插入突变与129Met等位基因连锁,并以杂合形式存在。同样的插入在女孩母亲的基因组中也有发现,而其父亲和同父异母兄长的PRNP基因正常。随后,德国Grasbon-Frodl等在CJD病人的PRNP基因中也发现了类似的3个八肽的插入突变,提示PrP8G是一种致病突变。我们
[Abstract]:Transmissible spongiform encephalopathy (TSE) is a rare, subacute fatal neurodegenerative disease in humans and animals, including mad cow disease. Sheep pruritus and human new variant Creutzfeldt-Jakob disease. TSEs are caused by the transformation of cellular prion protein (PrP~C) into pathogenic prion protein (PrPnsca), so they are also called prion disease. There are many kinds of human prion diseases, 10-15% of which can be inherited. It is related to the mutation of human prion protein gene PRNP, and 85% is sporadic. The mechanism of sporadic prion disease is not clear. The analysis has proved that M129V and E219K polymorphisms are closely related to the susceptibility of prion disease. Moreover, the frequency of M 129V and E 219K genotypes and alleles varied greatly among different ethnic groups. In order to understand the distribution of PRNP genotype and allele frequency in China, we investigated M129V and E219K polymorphisms of PRNP gene in 626 normal subjects, including Han nationality. We found that the distribution of the 129m / M homozygote genotype in the three ethnic groups was significantly different. The frequency of 129M / M genotype was the highest in Han nationality, followed by Hui nationality (8510) and Uygur nationality (60m / M), which was much higher than that of European population (129M / M). The highest frequency of 219E / E genotype was in Uygur nationality, followed by Hui nationality (96th) and Han nationality (909m / M). One result suggests that our population may be more susceptible to prion disease than the European population. We also analyzed two other rare PRNP polymorphism loci: A117A and octopeptide repeats with the deletion of an octopeptide unit. We found A117A resting mutation GCA in three Uygur subjects. 鈫扵he heterozygous 1-OPRD mutation was found in 4 Hui individuals (2. 0) and 1 Han individual (0. 5). Sequence analysis of PRNP gene is an important way to find genetic prion disease. We first found a new mutation of prion inserted into three extra octopeptide copies of 72bp. by cloning and sequencing. The gene sequence named PrP8G.PrP8G octopeptide repeats is R1, R2, R2, R2, R2, R2, R2, R2, R4, and the wild type sequence, R1, R2, R2, R2, R3, of which there are three copies of R2a R2R2 and R3. The results of sequencing also show that the inserted mutation is linked to the 129Met allele. The same insert was found in the genome of the girl's mother, and the PRNP gene of her father and half brother was normal. Three similar octopeptide insertions were found in the PRNP gene of CJD patients by Grasbon-Frodl et al in Germany, suggesting that PrP8G is a pathogenic mutation.
【学位授予单位】：武汉大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：Q987;R373

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