与NSML相关的RAS病变中的SHP2基因变异破坏了PZR-IRX转录因子信号轴
Sravan Perla1, Amy L Stiegler1, Jae-Sung Yi1
1Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
概括
通过影响SHP2向PZR的招募,导致IRX和BMP10水平的改变,破坏了多个lentigines (NSML) 的Noonan综合征. 针对这种途径可以治疗与RAS病相关的缩性心肌病 (HCM).
科学领域:
- 心血管生物学
- 遗传学
- 分子医学
背景情况:
- 诺南综合征与多种虫 (NSML) 是一种与PTPN11突变相关的遗传疾病.
- 大多数NSML患者患有多变性心肌病 (HCM),这是一个重要的临床挑战.
- 将NSML与HCM联系在一起的分子机制需要进一步阐明.
研究的目的:
- 研究SHP2对PZR在NSML相关心脏缩中的作用.
- 确定涉及IRX转录因子和BMP10在NSML病变的信号通路.
- 探索与NSML相关的潜在治疗点.
主要方法:
- 使用了具有特定PZR突变的NSML小鼠模型和低剂量达沙替尼治疗.
- 通过结构研究分析了蛋白与蛋白的相互作用,包括SHP2-PZR和SHP2-c-Src结合.
- 心脏组织中IRX3,IRX5和BMP10的量化基因和蛋白质表达水平.
主要成果:
- 对于NSML心脏表型来说,SHP2对基化PZR的招募至关重要.
- 这种相互作用调节了抑制BMP10的Iroquois homeobox (IRX) 转录因子 (IRX3和IRX5).
- 功能障碍的SHP2- PZR相互作用会影响IRX激活,导致BMP10升高和心脏缩.
- 在NSML小鼠中,达沙替尼治疗使IRX和BMP10水平正常化.
结论:
- 与NSML相关的SHP2变种破坏了PZR-SHP2-IRX-BMP10信号轴.
- 这一轴是产后心脏生长的关键调节器,与NSML- HCM有关.
- 针对PZR-SHP2相互作用或下游信号提供了与RAS病相关的HCM的潜在治疗策略.
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