Genetic susceptibility to Prion diseases in humans and mice
Genetic susceptibility to Prion diseases in humans and mice
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DOI：
10.2174/1389202053202166
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发表时间：
2005-02-01
期刊：
影响因子：
2.6
通讯作者：
Collinge, J
中科院分区：
文献类型：
--
作者：
Lloyd, SE;Collinge, J
朊病毒疾病是动物和人类致命的传染性神经退行性疾病，与潜伏期延长有关，包括瘙痒症、牛海绵状脑病（BSE）和克雅氏病（CJD）。变异型克雅氏病（vCJD）的出现以及人们认识到它与疯牛病有因果关系，而疯牛病在饮食中广泛存在，这引起了相当大的公共卫生问题。根据纯蛋白质假说，朊病毒主要或完全由宿主编码的细胞朊蛋白（PrPC）的异常同种型（PrPSc）组成。人类朊病毒疾病有遗传性、散发性和获得性病因。遗传性朊病毒病都与人类PrP基因（PRNP）的编码突变有关。已知PrP多态性影响易感性、潜伏期和疾病表型。虽然PRNP是朊病毒疾病易感性的主要遗传决定因素，但越来越清楚的是，其他基因也起着重要作用。人类的遗传学研究受到受影响个体数量少的限制，因此为了鉴定这些基因，已经分析了几个大型小鼠杂交，并且现在鉴定了至少八个不同染色体上的多个基因座。到目前为止，确定的区域很大，候选基因的识别仍然具有挑战性。然而，替代小鼠杂交的发展提供了精细定位的前景，其与微阵列分析和增加的序列信息一起，现在使得鉴定这些易感基因成为现实的目标。这些小鼠等位基因的特征，然后他们的人类同源物可能允许识别BSE朊病毒感染的风险个体，允许更好地预测任何vCJD流行病，并最终应确定新的蛋白质和生化途径，这将有助于我们了解朊病毒的发病机制，并提供新的治疗干预的目标。
Prion diseases are fatal transmissible neurodegenerative disorders of both animals and humans associated with prolonged incubation periods and include scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease (CJD). The arrival of variant CJD (vCJD) and the recognition that it is causally related to BSE, to which there has been widespread dietary exposure, has lead to considerable public health concerns. According to the protein-only hypothesis, prions are principally or entirely composed of an abnormal isoform (PrPSc) of host-encoded cellular prion protein (PrPC). Human prion diseases have inherited, sporadic and acquired aetiologies. The inherited prion diseases are all associated with coding mutations in the human PrP gene (PRNP.) and PrP polymorphisms are known to affect susceptibility, incubation time and disease phenotype. Although PRNP is the major genetic determinant of prion disease susceptibility, it is becoming clear that other genes play an important role. Genetic studies in humans are limited by the small numbers of affected individuals and therefore to identify these genes several large mouse crosses have been analysed and multiple loci on at least eight different chromosomes now identified. To date, the regions identified are large and the identification of candidate genes remains challenging. However, the development of alternative mouse crosses offers the prospect of fine mapping, which, together with microarray analysis and increased sequence information, now makes identifying these susceptibility genes a realistic goal. Characterisation of these mouse alleles and then their human homologues may allow the identification of at-risk individuals for BSE prion infection, allow better prediction of any vCJD epidemic, and ultimately should identify new proteins and biochemical pathways which will contribute to our understanding of prion pathogenesis and provide new targets for therapeutic intervention.