Somatic Mosaicism in a Case of Apparently Sporadic Creutzfeldt-Jakob Disease Carrying a De Novo D178N Mutation in the PRNP Gene
Somatic Mosaicism in a Case of Apparently Sporadic Creutzfeldt-Jakob Disease Carrying a De Novo D178N Mutation in the PRNP Gene
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DOI：
10.1002/ajmg.b.31099
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发表时间：
2010-10-01
影响因子：
2.8
通讯作者：
Lopez de Munain, A.
中科院分区：
文献类型：
--
作者：
Alzualde, A.;Moreno, F.;Lopez de Munain, A.
传染性海绵状脑病是一组罕见的致死性神经退行性疾病。克雅氏病（CJD）是TSE最常见的形式，可分为散发性、遗传性、医源性和变异型。遗传病例与朊蛋白基因突变有关，但仅占病例的10-20%。在这里，我们报告一例明显散发的CJD病例，阴性家族史携带在密码子178突变的朊蛋白基因。这种突变是一种新生突变，因为该病例的父母没有表现出这种突变。此外，通过不同的方法证实了三种不同等位基因（野生型129M-178D和129V-178D以及突变的129V-178N）的存在，表明这种新生突变是一种产生体细胞嵌合体的合子后突变。外周血细胞和脑组织中突变细胞的比例相似，估计约为97%，表明突变发生在胚胎发生的早期阶段。神经病理学检查显示，主要累及尾状核、壳核和大脑皮层的海绵状改变，同时在大脑和小脑中可见抗蛋白酶k型PrP球形沉积。PrP分型以21 kDa的低带为特征。这是在朊病毒疾病中描述的第一例嵌合现象，并说明了明显散发的神经退行性疾病的潜在病因。鉴于这种情况，遗传性和散发形式的传染性脑病的遗传咨询应考虑到遗传筛查程序的这种可能性。(c) 2010 Wiley-Liss, Inc。
Transmissible spongiform encephalopathies (TSEs) are a group of rare fatal neurodegenerative disorders. Creutzfeldt-Jakob disease (CJD) represents the most common form of TSE and can be classified into sporadic, genetic, iatrogenic and variant forms. Genetic cases are related to prion protein gene mutations but they only account for 10-20% of cases. Here we report an apparently sporadic CJD case with negative family history carrying a mutation at codon 178 of prion protein gene. This mutation is a de novo mutation as the parents of the case do not show it. Furthermore the presence of three different alleles (wild type 129M-178D and 129V-178D and mutated 129V-178N), confirmed by different methods, indicates that this de novo mutation is a post-zygotic mutation that produces somatic mosaicism. The proportion of mutated cells in peripheral blood cells and in brain tissue was similar and was estimated at approximately 97%, suggesting that the mutation occurred at an early stage of embryogenesis. Neuropathological examination disclosed spongiform change mainly involving the caudate and putamen, and the cerebral cortex, together with proteinase K-resistant PrP globular deposits in the cerebrum and cerebellum. PrP typing was characterized by a lower band of 21 kDa. This is the first case of mosaicism described in prion diseases and illustrates a potential etiology for apparently sporadic neurodegenerative diseases. In light of this case, genetic counseling for inherited and sporadic forms of transmissible encephalopathies should take into account this possibility for genetic screening procedures. (c) 2010 Wiley-Liss, Inc.