本文關(guān)鍵詞： 人朊病毒病 PRNP基因 基因多態(tài)性 插入突變 蛋白聚集　出處：《武漢大學》2005年博士論文　論文類型：學位論文

【摘要】：可傳播性海綿狀腦病(TSE)是人和動物的一類罕見的、亞急性致死性神經(jīng)退化疾病,包括瘋牛病、羊搔癢病和近年來出現(xiàn)的人新型變異克雅氏病等。TSEs由細胞型朊病毒蛋白PrP~C轉(zhuǎn)變成致病型朊病毒蛋白PrP~(Sc)引起,因此也稱朊病毒病。人的朊病毒病有多種,其中10—15%可以遺傳,并與人的朊病毒蛋白基因PRNP的突變有關(guān),另有85%呈散發(fā)性。散發(fā)型朊病毒病的具體發(fā)生機制尚不清楚。已有的分析證明,PRNP基因的M129V和E219K多態(tài)性與朊病毒病的易感性關(guān)系密切,而且不同種族人群的M129V和E219K基因型和等位基因頻率差異很大。 為了解我國PRNP基因型和等位基因頻率的分布,我們調(diào)查了總計626例正常人的PRNP基因的M129V和E219K多態(tài)性,包括漢族、回族和維吾爾族三個民族的人群。我們發(fā)現(xiàn)129M/M純合子基因型在三個民族中的分布明顯不同,漢族129M/M基因型頻率最高(98%),其次是回族(85%),最低為維吾爾族(60%),均大大高于歐洲人群的129M/M基因型頻率。而219E/E的基因型頻率最高的是維吾爾族(98%),其次為回族(96%)和漢族(90%)。這一結(jié)果提示我國人群可能較歐洲人群對朊病毒病更為易感。此外,我們還分析了另外兩個較為少見的PRNP多態(tài)性位點:A117A和八肽重復區(qū)缺失一個八肽單位的突變(1-OPRD)。我們在3例維吾爾族個體中發(fā)現(xiàn)了A117A靜息突變(gca→gcg);在4例回族個體(2.0%)和1例漢族個體(0.5%)中發(fā)現(xiàn)了雜合的1-OPRD突變。 PRNP基因序列分析是發(fā)現(xiàn)遺傳型朊病毒病的重要途徑。我們用克隆測序的方法首次發(fā)現(xiàn)了插入3個額外八肽拷貝(72bp)的朊病毒新突變,并將其命名為PrP8G。PrP8G八肽重復區(qū)的基因序列是R1、R2、R2、R2a、R2、R2、R3、R4,與野生型序列(R1、R2、R2、R3、R4)對照,突變序列在R2和R3之間多出了R2a、R2、R2三個八肽拷貝,測序的結(jié)果還顯示這一插入突變與129Met等位基因連鎖,并以雜合形式存在。同樣的插入在女孩母親的基因組中也有發(fā)現(xiàn),而其父親和同父異母兄長的PRNP基因正常。隨后,德國Grasbon-Frodl等在CJD病人的PRNP基因中也發(fā)現(xiàn)了類似的3個八肽的插入突變,提示PrP8G是一種致病突變。我們
[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.
【學位授予單位】：武漢大學
【學位級別】：博士
【學位授予年份】：2005
【分類號】：Q987;R373

【引證文獻】

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1 夏勝利;韓俊;史曉紅;謝志強;申曉靖;高晨;周偉;張杰文;張錦;董小平;許汴利;;河南省致死性家族失眠癥家系遺傳生物學分析[J];中國公共衛(wèi)生;2011年06期

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本文編號：1526760