Lloyd Sarah E, Uphill James B, Targonski Paul V, Fisher Elizabeth M C, Collinge John
MRC Prion Unit, Department of Neurodegenerative Diseases, Institute of Neurology, University College, London, W21N 3BG, UK.
Neurogenetics. 2002 Oct;4(2):77-81. doi: 10.1007/s10048-002-0133-9.
Prion diseases are fatal neurodegenerative disorders of humans and animals, which include bovine spongiform encephalopathy (BSE) and its human form, variant Creutzfeldt-Jakob disease (vCJD). They are characterized by a prolonged incubation period, which is known to be influenced by polymorphisms in the prion protein gene. Previous studies of inbred mice have demonstrated that additional genetic loci also contribute to the observed variation in incubation period. However, a substantial transmission barrier between cow and mouse complicates studies using BSE. As a result, primary transmissions display large variations in incubation period and not all animals develop clinical signs of disease. To identify quantitative trait loci for BSE without the presence of a transmission barrier, we analysed 124 animals from an F2 intercross between CAST/Ei and NZW/OlaHsd mice and challenged them intracerebrally with a strain of BSE that was passaged twice through C57BL/6OlaHsd mice. Interval mapping identified two highly significant linked regions on chromosomes 2 and 11 with peak lod scores of 6.34 and 4.77, respectively. Composite interval mapping suggests that chromosome 2 includes three linked quantitative trait loci. Loci in the same position on chromosomes 2 and 11 were also identified in a previous study using the same mouse cross but infected with Chandler/RML scrapie prions. If these are the same loci, it suggests that these loci may be influencing incubation time independently of prion strain. This provides hope that it may be possible to identify human quantitative trait loci for prion incubation time using mouse models that may allow identification of at-risk individuals and the discovery of novel therapeutic targets.
朊病毒病是人和动物的致命性神经退行性疾病，包括牛海绵状脑病（BSE）及其人类形式变异型克雅氏病（vCJD）。它们的特点是潜伏期长，已知这会受到朊病毒蛋白基因多态性的影响。此前对近交系小鼠的研究表明，其他基因位点也会导致观察到的潜伏期差异。然而，牛和小鼠之间存在巨大的传播障碍，这使得使用BSE进行研究变得复杂。因此，初次传播时潜伏期差异很大，并非所有动物都会出现疾病的临床症状。为了在不存在传播障碍的情况下鉴定BSE的数量性状基因座，我们分析了CAST/Ei和NZW/OlaHsd小鼠杂交产生的F2代中的124只动物，并通过脑内接种经过C57BL/6OlaHsd小鼠传代两次的BSE毒株对它们进行攻击。区间定位在2号和11号染色体上确定了两个高度显著的连锁区域，峰值对数优势分数分别为6.34和4.77。复合区间定位表明2号染色体包含三个连锁的数量性状基因座。在之前一项使用相同小鼠杂交组合但感染Chandler/RML羊瘙痒病朊病毒的研究中，也在2号和11号染色体的相同位置鉴定到了基因座。如果这些是相同的基因座，这表明这些基因座可能独立于朊病毒毒株影响潜伏期。这带来了希望，即有可能利用小鼠模型鉴定出人类朊病毒潜伏期的数量性状基因座，这可能有助于识别高危个体并发现新的治疗靶点。
