PDF(Pubmed)
Abstract：
As binary switches, RAS proteins switch to an ON/OFF state during signaling and are on a leash under normal conditions. However, in RAS-related diseases such as cancer and RASopathies, mutations in the genes that regulate RAS signaling or the RAS itself permanently activate the RAS protein. The structural basis of this switch is well understood; however, the exact mechanisms by which RAS proteins are regulated are less clear. RAS/MAPK syndromes are multisystem developmental disorders caused by germline mutations in genes associated with the RAS/mitogen-activated protein kinase pathway, impacting 1 in 1,000-2,500 children. These include a variety of disorders such as Noonan syndrome (NS) and NS-related disorders (NSRD), such as cardio facio cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML, also known as LEOPARD syndrome). A frequent manifestation of cardiomyopathy (CM) and hypertrophic cardiomyopathy associated with RASopathies suggest that RASopathies could be a potential causative factor for CM. However, the current supporting evidence is sporadic and unclear. RASopathy-patients also display a broad spectrum of congenital heart disease (CHD). More than 15 genes encode components of the RAS/MAPK signaling pathway that are essential for the cell cycle and play regulatory roles in proliferation, differentiation, growth, and metabolism. These genes are linked to the molecular genetic pathogenesis of these syndromes. However, genetic heterogeneity for a given syndrome on the one hand and alleles for multiple syndromes on the other make classification difficult in diagnosing RAS/MAPK-related diseases. Although there is some genetic homogeneity in most RASopathies, several RASopathies are allelic diseases. This allelism points to the role of critical signaling nodes and sheds light on the overlap between these related syndromes. Even though considerable progress has been made in understanding the pathophysiology of RASopathy with the identification of causal mutations and the functional analysis of their pathophysiological consequences, there are still unidentified causal genes for many patients diagnosed with RASopathies.
摘要：
作为二进制开关，RAS蛋白在信号传导过程中切换到ON/OFF状态，并且在正常条件下处于皮带状态。然而,在RAS相关疾病，如癌症和放射病，调节RAS信号传导的基因或RAS本身的突变会永久激活RAS蛋白。这种转换的结构基础是众所周知的；然而，RAS蛋白调控的确切机制尚不清楚.RAS/MAPK综合征是由RAS/丝裂原活化蛋白激酶通路相关基因的种系突变引起的多系统发育障碍,影响1/1-2,000儿童。这些包括各种疾病，如努南综合征（NS）和NS相关疾病（NSRD），例如心脏皮肤（CFC）综合征，科斯特洛综合征（CS），和具有多个腹水的NS(NSML，也称为LEOPARD综合征）。与放射病相关的心肌病（CM）和肥厚型心肌病的频繁表现表明，放射病可能是CM的潜在致病因素。然而,目前的支持证据是零星和不清楚的。RASopathy患者还表现出广泛的先天性心脏病（CHD）。超过15个基因编码RAS/MAPK信号通路的成分，这些成分对细胞周期至关重要，并在增殖中起调节作用。分化,增长,和新陈代谢。这些基因与这些综合征的分子遗传发病机制有关。然而,一方面是给定综合征的遗传异质性，另一方面是多个综合征的等位基因，这使得分类难以诊断RAS/MAPK相关疾病。尽管在大多数拉丝菌中存在一些遗传同质性，几种放射病是等位基因疾病。这种等位基因指向关键信号节点的作用，并揭示了这些相关综合征之间的重叠。尽管通过识别因果突变和对其病理生理后果的功能分析，在理解RASpathy的病理生理学方面取得了相当大的进展，对于许多被诊断为放射病的患者,仍然存在未知的因果基因.
