NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT.
NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT.
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DOI：
10.1016/j.bbadis.2010.10.002
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发表时间：
2011-01
影响因子：
6.2
通讯作者：
Cole, Susan E.
中科院分区：
文献类型：
--
作者：
Riley, Maurisa F.;McBride, Kim L.;Cole, Susan E.
关键词：
缺口信号对于心脏的正常发育是必不可少的。我们最近在不同的左心室流出道(LVOT)畸形(NOTCH1G661S和NOTCH1A683T)患者中发现了NOTCH1受体的错义变体，这些错义变体减少了配体诱导的Notch信号。在这里，我们研究了导致信号减少和发育受扰的分子机制。我们发现NOTCH1A683T由于通过内质网(ER)的运输受损而导致S1裂解减少。这一观察结果与变异型受体对内质网的错误定位和细胞表面呈现减少一致。相反，附近的突变NOTCH1G661S在没有明显折叠或运输缺陷的情况下，细胞表面呈现减少。为了研究这些变异在疾病发病机制中的意义，我们调查了它们对上皮间充质转化(EMT)的影响，EMT是流出道发育的关键过程。我们发现，这些与LVOT相关的NOTCH1等位基因可能通过削弱对Snail和Hes家族成员的诱导而导致内皮细胞系EMT缺陷。这些数据首次描述了LVOT畸形个体中NOTCH1突变的分子机制，并对这些等位基因对一系列复杂的发育缺陷的功能贡献具有重要意义。
Notch signaling is essential for proper cardiac development. We recently identified missense variants in the NOTCH1 receptor in patients with diverse left ventricular outflow tract (LVOT) malformations (NOTCH1G661S and NOTCH1A683T) that reduce ligand-induced Notch signaling. Here, we examine the molecular mechanisms that contribute to reduced signaling and perturbed development. We find that NOTCH1A683T exhibits reduced S1 cleavage due to impaired trafficking through the endoplasmic reticulum (ER). This observation is consistent with improper localization of the variant receptor to the ER and decreased presentation at the cell surface. In contrast, the nearby mutation NOTCH1G661S exhibits reduced cell-surface presentation in the absence of overt folding or trafficking defects. To examine the implications of these variants in disease pathogenesis, we investigated their effect on epithelial-to-mesenchymal transition (EMT), a critical process for development of the outflow tract. We find that these LVOT-associated NOTCH1 alleles can contribute to defective EMT in endothelial cell lines through impaired induction of Snail and Hes family members. These data represent the first description of a molecular mechanism underlying NOTCH1 mutations in individuals with LVOT malformations, and have important implications regarding the functional contribution of these alleles to a complex set of developmental defects.
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影响因子：
3.7
作者：
Gordon WR;Vardar-Ulu D;L'Heureux S;Ashworth T;Malecki MJ;Sanchez-Irizarry C;McArthur DG;Histen G;Mitchell JL;Aster JC;Blacklow SC
通讯作者：
Blacklow SC
DOI：
10.1016/j.biocel.2008.10.001
发表时间：
2009-05
影响因子：
4
作者：
Luther, Kelvin B.;Haltiwanger, Robert S.
通讯作者：
Haltiwanger, Robert S.
DOI：
10.1002/bdra.20169
发表时间：
2005-08-01
影响因子：
--
作者：
McBride, KL;Marengo, L;Belmont, JW
通讯作者：
Belmont, JW
影响因子：
4.8
作者：
Jehn, BM;Dittert, I;Bielke, W
通讯作者：
Bielke, W
影响因子：
15.9
作者：
High, Frances A.;Jain, Rajan;Epstein, Jonathan A.
通讯作者：
Epstein, Jonathan A.