HECTD2 is associated with susceptibility to mouse and human prion disease.
HECTD2 is associated with susceptibility to mouse and human prion disease.
复制标题
HECTD2与小鼠和人类prion病的敏感性有关。
DOI：
10.1371/journal.pgen.1000383
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发表时间：
2009-02
期刊：
影响因子：
4.5
通讯作者：
Collinge J
中科院分区：
文献类型：
--
作者：
Lloyd SE;Maytham EG;Pota H;Grizenkova J;Molou E;Uphill J;Hummerich H;Whitfield J;Alpers MP;Mead S;Collinge J
朊病毒病是一种致命的传染性神经退行性疾病，包括羊瘙痒病、牛海绵状脑病（BSE）、克雅氏病（CJD）和库鲁病。它们的特征是延长的临床无症状潜伏期，其中的变化由许多因素决定，包括遗传背景。我们已经使用了一个异质性股票的小鼠，以确定Hectd 2，E3泛素连接酶，作为一个数量性状基因的小鼠朊病毒疾病的潜伏期。此外，我们报告了HECTD 2单倍型和获得性人类朊病毒疾病，vCJD和库鲁病的易感性之间的关联。我们报告了一个基因型相关的差异表达Hectd 2 mRNA在小鼠脑和人类淋巴细胞和一个显着的上调转录在小鼠在朊病毒疾病的末期。虽然HECTD 2的底物是未知的，但这些数据突出了蛋白体指导的蛋白质降解在神经变性中的重要性。这是第一次证明小鼠数量性状基因也影响人类朊病毒疾病的易感性。这些基因的特征是理解人类风险和潜伏期的分子基础的关键。朊病毒病是动物和人类的致命性传染性神经退行性疾病，目前尚无治疗方法。它们包括牛海绵状脑病（BSE）及其人类等价物，变异型克雅氏病（vCJD）。朊病毒疾病的特征是在疾病出现之前有一个漫长而沉默的潜伏期，并且这个时间间隔在个体之间差异很大。我们基因组成的差异是这种变异性的关键因素。我们已经知道，一个关键基因（朊病毒蛋白基因）内的自然变异对潜伏期有重大影响，但现在很清楚，许多其他基因也很重要。使用小鼠模型，我们已经确定了这些基因之一，Hectd 2，它被认为参与了从细胞中去除不需要的蛋白质的过程。我们还发现，HECTD 2与两种人类朊病毒疾病的风险增加有关-英国的vCJD和巴布亚新几内亚的库鲁病。这些数据将使我们更好地了解这些疾病的基本过程，并在一定程度上解释为什么一些暴露于BSE的个体会发展为vCJD，而另一些则没有。
Prion diseases are fatal transmissible neurodegenerative disorders, which include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru. They are characterised by a prolonged clinically silent incubation period, variation in which is determined by many factors, including genetic background. We have used a heterogeneous stock of mice to identify Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation time in mice. Further, we report an association between HECTD2 haplotypes and susceptibility to the acquired human prion diseases, vCJD and kuru. We report a genotype-associated differential expression of Hectd2 mRNA in mouse brains and human lymphocytes and a significant up-regulation of transcript in mice at the terminal stage of prion disease. Although the substrate of HECTD2 is unknown, these data highlight the importance of proteosome-directed protein degradation in neurodegeneration. This is the first demonstration of a mouse quantitative trait gene that also influences susceptibility to human prion diseases. Characterisation of such genes is key to understanding human risk and the molecular basis of incubation periods. Prion diseases are fatal transmissible neurodegenerative diseases of animals and humans for which there is no treatment. They include Bovine Spongiform Encephalopathy (BSE), and its human equivalent, variant Creutzfeldt-Jakob Disease (vCJD). Prion diseases are characterised by a long, silent incubation period before the disease emerges, and this time interval varies greatly between individuals. Differences in our genetic makeup are a key factor in this variability. We already know that natural variation within one key gene, the prion protein gene, has a major influence on incubation time, but it is now clear that a number of other genes are also important. Using a mouse model, we have identified one of these genes, Hectd2, which is thought to be involved in the process that removes unwanted proteins from the cell. We also show that HECTD2 is associated with an increased risk of two human prion diseases—vCJD in the United Kingdom and kuru in Papua New Guinea. These data will give us a better understanding of the fundamental processes involved in these diseases and go some way to explaining why some individuals exposed to BSE have developed vCJD and others have not.
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影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
56.9
作者：
He, L;Lu, XY;Gunn, TM
通讯作者：
Gunn, TM
DOI：
10.1073/pnas.230304397
发表时间：
2000-11-07
影响因子：
11.1
作者：
Mott, R;Talbot, CJ;Flint, J
通讯作者：
Flint, J
影响因子：
2.6
作者：
Lloyd, SE;Collinge, J
通讯作者：
Collinge, J
影响因子：
56.9
作者：
Mead, S;Stumpf, MPH;Collinge, J
通讯作者：
Collinge, J