Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.
Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.
复制标题
DOI：
10.1038/ncomms1633
复制
发表时间：
2012-01-10
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
HHT是由TGF-β/BMP通路基因ENG和ACVRL1突变引起的血管发育不良综合征。HHT在临床表现上有相当大的差异，提示环境和/或基因修饰因素的影响。Eng+/ -和Tgfb1 - / -小鼠血管表型的株特异性外显率为TGF-β通路缺陷的基因修饰提供了进一步的支持。我们之前发现了包括Tgfbm2在内的变异基因组位点，它们抑制Tgfb1−/−小鼠的产前血管死亡率。本研究表明，通过肺动静脉畸形的发展来评估，同源TGFBM2基因座内PTPN14的人类多态性变异会影响HHT的临床严重程度。我们还发现编码EphrinB2的PTPN14、ACVRL1和EFNB2在体外原代动脉内皮细胞中相互依赖表达。这表明PTPN14通过EphrinB2和ACVRL/Alk-1参与血管生成和/或动静脉命运。这些发现有助于更深入地了解HHT的分子病理学，特别是血管生成。
HHT is a vascular dysplasia syndrome caused by mutations in TGF-β/BMP pathway genes, ENG and ACVRL1. HHT shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng+/− and Tgfb1−/− mice provides further support for genetic modification of TGF-β pathway deficits. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1−/− mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HHT, as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL/Alk-1. These findings contribute to a deeper understanding of the molecular pathology of HHT in particular and to angiogenesis in general.
登录
查看更多内容
影响因子：
2.7
作者：
Arthur, HM;Ure, J;Diamond, AG
通讯作者：
Diamond, AG
影响因子：
2
作者：
Gallione, Carol;Aylsworth, Arthur S.;Marchuk, Douglas A.
通讯作者：
Marchuk, Douglas A.
影响因子：
16
作者：
Goumans, MJ;Valdimarsdottir, G;ten Dijke, P
通讯作者：
ten Dijke, P
影响因子：
11.4
作者：
Goumans, MJ;Valdimarsdottir, G;ten Dijke, P
通讯作者：
ten Dijke, P
影响因子：
9.8
作者：
Au, Audrey C.;Hernandez, Paolo A.;Diaz, George A.
通讯作者：
Diaz, George A.