Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches.
Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches.
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DOI：
10.1007/s00702-013-1142-6
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发表时间：
2014-05
影响因子：
3.3
通讯作者：
Walss-Bass, Consuelo
中科院分区：
文献类型：
--
作者：
Marballi, Ketan K.;McCullumsmith, Robert E.;Yates, Stefani;Escamilla, Michael A.;Leach, Robin J.;Raventos, Henriette;Walss-Bass, Consuelo
神经调节蛋白1-ErbB 4信号异常与精神分裂症有关。我们以前确定了一种新的精神分裂症相关的错义突变（缬氨酸亮氨酸）在NRG 1跨膜结构域。这种变体抑制NRG 1胞内结构域（ICD）的形成，并导致树突形成减少。为了评估该突变的总体效应，我们使用了来自未受影响的杂合携带者（瓦尔/Leu）和非携带者（瓦尔/瓦尔）的淋巴母细胞样细胞系。转录组数据显示两组之间有367个基因差异表达（瓦尔/瓦尔N=6，瓦尔/Leu N=5，T检验，FDR（1%），α = 0.05，− log 10 p值> 1.5）。免疫途径（IPA）分析显示炎症和NRG 1信号传导作为顶级途径发生了改变。在NRG 1信号传导中，蛋白激酶C（PKC）-eta（PRKCH）和非受体酪氨酸激酶（SRC）在杂合携带者中下调。在用ErbB 4刺激细胞（V/V N=6，V/L N=6）以诱导NRG 1 ICD的释放后，进行新的激酶组分析（丝氨酸/苏氨酸），并揭示了处理对35种肽的磷酸化的显著影响。IPA显示神经突生长（6个肽）作为最高注释功能。ErbB 4处理的瓦尔/瓦尔细胞中这些肽的磷酸化显著降低，但在瓦尔/Leu细胞中没有。这些结果表明，干扰NRG 1 ICD的形成有重大影响的细胞信号传导，包括炎症和神经突形成途径，并可能有助于显着精神分裂症的病理生理。
Aberrant Neuregulin 1-ErbB4 signalling has been implicated in schizophrenia. We previously identified a novel schizophrenia-associated missense mutation (valine to leucine) in the NRG1 transmembrane domain. This variant inhibits formation of the NRG1 intracellular domain (ICD) and causes decreases in dendrite formation. To assess the global effects of this mutation we used lymphoblastoid cell lines from unaffected heterozygous carriers (Val/Leu) and non carriers (Val/Val). Transcriptome data showed 367 genes differentially expressed between the two groups (Val/Val N=6, Val/Leu N=5, T test, FDR (1%), alpha = 0.05, −log10 p value > 1.5). Ingenuity pathway (IPA) analyses showed inflammation and NRG1 signalling as the top pathways altered. Within NRG1 signalling, Protein Kinase C (PKC)–eta (PRKCH) and non-receptor tyrosine kinase (SRC) were down-regulated in heterozygous carriers. Novel kinome profiling (Serine/Threonine) was performed after stimulating cells (V/V N=6, V/L N=6) with ErbB4, to induce release of the NRG1 ICD, and revealed significant effects of treatment on the phosphorylation of 35 peptides. IPA showed neurite outgrowth (6 peptides) as the top annotated function. Phosphorylation of these peptides was significantly decreased in ErbB4-treated Val/Val but not in Val/Leu cells. These results show that perturbing NRG1 ICD formation has major effects on cell signalling, including inflammatory and neurite formation pathways, and may contribute significantly to schizophrenia pathophysiology.
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DOI：
10.1523/jneurosci.1815-08.2008
发表时间：
2008-07-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen YJ;Johnson MA;Lieberman MD;Goodchild RE;Schobel S;Lewandowski N;Rosoklija G;Liu RC;Gingrich JA;Small S;Moore H;Dwork AJ;Talmage DA;Role LW
通讯作者：
Role LW
影响因子：
7.8
作者：
Bao, JX;Wolpowitz, D;Role, LW;Talmage, DA
通讯作者：
Talmage, DA
影响因子：
4.6
作者：
Hancock, Melissa L.;Nowakowski, Dan W.;Flanagan, John G.
通讯作者：
Flanagan, John G.
影响因子：
3.3
作者：
Glausier, J. R.;Lewis, D. A.
通讯作者：
Lewis, D. A.
影响因子：
4.5
作者：
Choy E;Yelensky R;Bonakdar S;Plenge RM;Saxena R;De Jager PL;Shaw SY;Wolfish CS;Slavik JM;Cotsapas C;Rivas M;Dermitzakis ET;Cahir-McFarland E;Kieff E;Hafler D;Daly MJ;Altshuler D
通讯作者：
Altshuler D