nature-genetic201211-10

来自美国约翰霍普金斯大学医学院的Harry Dietz及其同事在Shprintzen-Goldberg综合征患者体内鉴定到SKI基因的突变。Shprintzen-Goldberg综合征是一种与马凡氏综合征(MFS)和洛伊迪茨综合征(LDS)具有共同症状的疾病。SKI编码了一个已知的、抑制TGF-β活性的阻遏蛋白。这项研究发现了一个矛盾的现象,即增强的TGF-β信号通路是这些相互关联的综合征的发病机制。相关的研究论文于9月30日在线发表在《Nature Genetics》期刊上。

-2012年11月《自然-遗传》

中文翻译


【题目】TGF-β阻遏基因SKI的突变引起伴有主动脉动脉瘤的Shprintzen-Goldberg综合征

【译文】已有研究表明增强的转化生长因子(TGF)-β信号参与了表现出主动脉动脉瘤的综合征的发病机制,这些综合征包括马凡氏综合征(MFS)和洛伊迪茨综合征(LDS)。然而,导致LDS综合征的许多致病基因突变的定位和特性都直观地暗示:TGF-β的信号通路受到抑制。总之,这些研究使得TGF-β在疾病的发病机理中所起的特殊作用具有极大的争议。Shprintzen-Goldberg综合征(SGS)与MFS和LDS具有相当多相同的表型,包括主动脉动脉瘤。我们在10例SGS患者的原癌基因SKI(因能抑制TGF-β的活性而出名)上鉴定到致病性突变。与正常细胞相比,体外培养的、来自受累者的真皮成纤维细胞具有活化增强的TGF-β信号级联反应及较高表达水平的TGF-β相应基因。吗啉代诱导沉默斑马鱼的SKI旁系同源基因,结果斑马鱼也出现与SGS患者一样的畸形特征。这些研究结果证实了这一结论:增强的TGF-β信号是SGS的发病机制,高强度的TGF-β信号能够导致伴有主动脉动脉瘤的多重综合征。

英文原稿


[Title]: Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm   

[Authors]: Alexander J Doyle, Jefferson J Doyle, Seneca L Bessling, Samantha Maragh, Mark E Lindsay, Dorien Schepers, Elisabeth Gillis, Geert Mortier, Tessa Homfray, Kimberly Sauls, Russell A Norris, Nicholas D Huso, Dan Leahy, David W Mohr, Mark J Caulfield, Alan F Scott, Anne Destrée, Raoul C Hennekam, Pamela H Arn, Cynthia J Curry, Lut Van Laer, Andrew S McCallion, Bart L Loeys & Harry C Dietz

[Abstract]: Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-β signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-β in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-β activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-β signaling cascades and higher expression of TGF-β–responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-β signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.

原文地址

http://www.nature.com/ng/journal/v44/n11/full/ng.2421.html

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