Frequency distribution of PRNP polymorphisms in the Pakistani population
Frequency distribution of PRNP polymorphisms in the Pakistani population
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DOI：
10.1016/j.gene.2011.10.029
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发表时间：
2012-01-15
期刊：
影响因子：
3.5
通讯作者：
Lone, Khalid P.
中科院分区：
文献类型：
--
作者：
Imran, Muhammad;Mahmood, Saqib;Lone, Khalid P.
朊病毒病是由正常宿主编码的朊病毒蛋白（PrPC）错误折叠成致病性羊瘙痒病朊病毒蛋白（PrPSc）引起的神经退行性疾病。在人类朊病毒疾病中，已知M129 V朊病毒蛋白多态性赋予疾病的易感性，决定PrPSc构象并改变临床病理表型。迄今为止，所有临床病理证实的变异型克-雅病（vCJD）病例均为129 MM纯合子。散发性CJD（sCJD）中129 MM纯合子也占优势。巴基斯坦没有提供有关朊病毒疾病的资料。虽然只有侵入性的程序，如脑活检可以确认朊病毒疾病的诊断，测试相应的人群中的朊病毒蛋白基因（PRNP）的变异可能会提供一些见解，这些疾病的存在，在一个地方。因此，目前的研究旨在探索巴基斯坦人群对克雅氏病的遗传易感性。共909无关的个人，包括221血友病患者代表所有4个主要省份的巴基斯坦进行了筛选M129 V多态性和插入或缺失的八肽重复序列（OPRI/OPRD），使用聚合酶链反应结合限制性片段长度多态性（PCR-RFLP）。双脱氧自动桑格测序也证实了一些PCR-RFLP反应结果的一致性。在909个个体中，M129 V等位基因（129 M和129 V）和基因型（129 MM、129 MV和129 VV）的频率分别为0.7101、0.2899、0.5270、0.3663和0.1067。10例PRNP杂合子和1例PRNP纯合子均检测到1个八肽重复序列（1-OPRD）缺失。在1个个体中发现了3个八肽重复序列（3-OPRI）的插入，在2个个体中发现了1个八肽重复序列（1-OPRI）的插入。3-OPRI和1-OPRI均为杂合子状态，与129 M等位基因连锁。健康人和血友病患者的M129 V等位基因频率和基因型频率之间没有显著差异。然而，M129 V等位基因和基因型频率在巴基斯坦人群与东亚和西方人群之间存在显著差异。健康个体和血友病患者的M129 V频率之间的非显著性卡方（2）差异表明，表现出单基因疾病的个体可能为旨在调查遗传变异的研究提供自然随机化样本。129 MM和129 W纯合性的组合过量和3-OPRI在1个个体中的存在意味着巴基斯坦人群易患朊病毒疾病。巴基斯坦可能存在朊病毒疾病病例，尽管其年发病率低于预期寿命超过65岁的其他国家。(C)2011 Elsevier B. V.保留所有权利。
Prion diseases are neurodegenerative conditions caused by misfolding of a normal host-encoded prion protein (PrPC) into pathogenic scrapie prion protein (PrPSc). In human prion diseases, the M129V prion protein polymorphism is known to confer susceptibility to the disease, determines PrPSc conformation and alters clinicopathological phenotypes. To date, all clinicopathologically confirmed cases of a variant form of Cruetz-feldt-Jacob disease (vCJD) have been 129MM homozygotes. There is also predominance of 129MM homozygotes in sporadic CJD (sCJD). No information regarding prion disorders is available from Pakistan. Although only invasive procedures like brain biopsy can confirm the diagnosis of prion disorders, testing a corresponding human population for variation in the prion protein gene (PRNP) may provide some insights into the presence of these disorders in a locality. The current study therefore aimed at exploring the genetic susceptibility of Pakistani population to CJD. A total of 909 unrelated individuals including 221 hemophiliacs representing all 4 major provinces of Pakistan were screened for M129V polymorphism and insertions or deletions of octapeptide repeats (OPRIs/OPRDs) using Polymerase Chain Reaction coupled with Restriction Fragment Length Polymorphism (PCR-RFLP). Concordance of the results of some PCR-RFLP reactions was also confirmed by dideoxy automated Sanger sequencing. The frequencies of M129V alleles (129M and 129V) and genotypes (129MM, 129MV and 129VV) were found in all 909 individuals to be 0.7101, 0.2899, 0.5270, 03663 and 0.1067, respectively. Deletion of 1 octapeptide repeat (1-OPRD) was detected in heterozygous state in PRNP of 10 individuals and in homozygous state in 1 individual. An insertion of 3 octapeptide repeats (3-OPRI) was found in 1 individual and an insertion of 1 octapeptide repeat (1-OPRI) in two individuals. Both 3-OPRI and 1-OPRI were present in heterozygous state and were linked to 129M allele. There were no significant,chi(2) differences between M129V allelic and genotypic frequencies of healthy individuals and hemophiliacs. However, M129V allelic and genotypic frequencies differed significantly between Pakistani population and East Asian and Western populations. Non-significant chi(2) differences between M129V frequencies of healthy individuals and hemophiliacs suggest that individuals manifesting single gene disorders may provide naturally randomized samples for studies aiming at surveying the genetic variation. The combined excess of 129MM and 129W homozygosity and the presence of 3-OPRI in 1 individual imply that Pakistani population is susceptible to prion disorders. Cases of prion disorders may exist in Pakistan, albeit at lower annual prevalence than other countries where life expectancy is greater than 65 years. (C) 2011 Elsevier B.V. All rights reserved.