Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers.
Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers.
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DOI：
10.1016/j.neurobiolaging.2014.04.016
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发表时间：
2014-10
影响因子：
4.2
通讯作者：
Rademakers R
中科院分区：
文献类型：
--
作者：
van Blitterswijk M;Mullen B;Heckman MG;Baker MC;DeJesus-Hernandez M;Brown PH;Murray ME;Hsiung GY;Stewart H;Karydas AM;Finger E;Kertesz A;Bigio EH;Weintraub S;Mesulam M;Hatanpaa KJ;White CL 3rd;Neumann M;Strong MJ;Beach TG;Wszolek ZK;Lippa C;Caselli R;Petrucelli L;Josephs KA;Parisi JE;Knopman DS;Petersen RC;Mackenzie IR;Seeley WW;Grinberg LT;Miller BL;Boylan KB;Graff-Radford NR;Boeve BF;Dickson DW;Rademakers R
9号染色体开放阅读框72(C9ORF72)的重复扩增是运动神经元病(MND)和额颞部痴呆(FTD)的重要原因。目前，对在C9ORF72扩展载体中检测到的表型异质性的影响因素知之甚少。在这项研究中，我们研究了四个可以代表遗传修饰物的基因：Aaxin-2(ATXN2)，非印记在Prader-Willi/Angelman综合征1(NIPA1)，存活运动神经元1(SMN1)和存活运动神经元2(SMN2)。在由331名C9ORF72扩张型携带者和376名对照组成的独特队列中，对这些基因的评估显示，ATXN2中的中间重复长度可能在C9ORF72扩张型携带者中扮演疾病修饰者的角色；没有证据表明NIPA1、SMN1或SMN2可能发挥作用。中间ATXN_2重复序列对MND或FTD/MND先证者的影响最大(2.1%比0%，P=0.013)，而FTD先证者的频率与对照组相同。虽然已经知道中间的ATXN2重复与MND风险有关，但以前的报告并没有关注具有明显致病突变的个体，例如C9ORF72的重复扩增。根据我们目前的发现，我们推测中间的ATXN2重复长度可能会使C9ORF72扩展载体更容易发生MND；然而，需要进一步的研究来验证我们的发现。
Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated four genes that could represent genetic modifiers: ataxin-2 (ATXN2), non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), survival motor neuron 1 (SMN1) and survival motor neuron 2 (SMN2). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 controls, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1, SMN1 or SMN2. The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% versus 0% in controls, P=0.013), whereas the frequency in probands with FTD was identical to controls. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72. Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings.
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影响因子：
30.8
作者：
Kim, Hyung-Jun;Raphael, Alya R.;LaDow, Eva S.;McGurk, Leeanne;Weber, Ross A.;Trojanowski, John Q.;Lee, Virginia M-Y;Finkbeiner, Steven;Gitler, Aaron D.;Bonini, Nancy M.
通讯作者：
Bonini, Nancy M.
影响因子：
4.2
作者：
Chen, YongPing;Huang, Rui;Shang, Hui-Fang
通讯作者：
Shang, Hui-Fang
DOI：
10.1083/jcb.201302044
发表时间：
2013-04-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Li YR;King OD;Shorter J;Gitler AD
通讯作者：
Gitler AD
影响因子：
9.9
作者：
Corcia, P.;Camu, W.;Andres, C. R.
通讯作者：
Andres, C. R.
影响因子：
9.9
作者：
van Blitterswijk, Marka;Baker, Matthew C.;Rademakers, Rosa
通讯作者：
Rademakers, Rosa