Gaining insights: the effects of the RMK gain-of-function mutations on brain development and neurodevelopmental disorders

项目摘要/摘要 罕见的遗传性疾病是人类发病的主要原因，经常影响大脑发育和病因 神经发育障碍。在此，我们建议使用Noonan综合征(NS，1：2000)作为人类模型 系统提供关于RAS/丝裂原活化蛋白激酶(RMK)-基因改变的影响的关键数据 关于人脑复杂系统级生物学的研究。三条证据支持将NS作为人类使用 模型系统：1)NS是由特定基因的高外显性常染色体显性突变引起的 与特发性神经发育障碍的遗传共同变异相比，2)NS有更大的影响 对大脑发育的影响，因此比特发性神经发育障碍的影响更大。 与神经发育障碍的风险增加有关，如注意力能力、学习能力 残疾和自闭症谱系症状。 我们实验室最近观察到PTPN11基因NS突变对人脑结构的影响， 特别是纹状体，和大脑功能，特别是额纹状体的连接。然而，有有限的 关于其他NS突变RAF1和SOS1对发育中的大脑的影响的数据。要解决这个问题 我们建议确定三个主要的NS疾病基因RAF1、PTPN11和SOS1 突变，与纹状体严重程度的改变有关。以提供有关 PTPN11基因变异与脑发育的关系，我们将检验PTPN11是否 致病变异与大脑发育改变有关。最后，我们将测试全脑是否 在NS中，连接性可以预测注意力能力。这一目标将为注意力能力提供一个神经标记物。 (具体地说，抑制)在NS。 我们将进行“深层表型”--纹状体的成像研究(体积、细胞密度、基于种子的 功能连接)和整个大脑(表面积、皮质厚度、白质、皮质髓鞘 内容和全脑功能连接)和评估儿童(7-16岁)的注意力(抑制) 年龄)与RAF1(n=30)、PTPN11(n=45)和SOS1(n=30)突变，并将它们与典型的 发展对照(n=45)。拟议工作的两个创新方面是使用限制谱 成像(RSI)定位RMK信号通路对纹状体细胞密度的上调作用。第二，我们将 首次评估RAF1突变对大脑发育的影响。 确定大脑和努南的遗传学之间的关系将加快基因测试的使用 告知NS的预后和治疗。此外，描述这些关系将提供有关 RMK在脑发育中的作用。

Project Summary/Abstract Rare genetic disorders are a major cause of human morbidity, frequently affect brain development and cause neurodevelopmental disorders. Here, we propose using Noonan syndrome (NS, 1:2000) as a human model system to provide critical data on the effects of Ras/mitogen-activated protein kinase (RMK)-genetic alterations on the human brain's complex systems-level biology. Three lines of evidence support using NS as a human model system: 1) NS is caused by autosomal dominant mutations of high penetrance in specific genes compared to idiopathic neurodevelopmental disorders genetics of common variance, 2) NS has a larger impact on brain development and thus larger effect sizes than idiopathic neurodevelopmental disorders, 3) NS is associated with increased risk for neurodevelopmental disorders such as attention abilities, learning disabilities, and autism spectrum symptoms. Our lab has recently observed the effect of NS mutations in the PTPN11 gene on human brain structure, specifically the striatum, and brain function, specifically frontostriatal connectivity. However, there is limited data available on the effect of other NS mutations, RAF1 and SOS1, on the developing brain. To address this limitation, we propose determining whether three major NS disease genes RAF1, PTPN11, and SOS1 mutations, are associated with striatal alteration in a gradient of severity. To provide critical data on the relationships between PTPN11 genetic variance and brain development, we will test whether PTPN11 pathogenic variants are associated with altered brain development. Finally, we will test whether whole-brain connectivity can predict attention abilities in NS. This aim will provide a neuromarker for attention abilities (specifically inhibition) in NS. We will perform "deep phenotyping" - imaging studies of the striatum (volume, cellular density, seed-based functional connectivity) and the whole brain (surface area, cortical thickness, white matter, cortical myelin content, and whole-brain functional connectivity) and assess attention (inhibition) in children (7-16 years of age) with RAF1 (n=30), PTPN11 (n=45), and SOS1 (n=30) mutations, and compare them to typically developing controls (n=45). Two innovative aspects of the proposed work are using restriction spectrum imaging (RSI) to map the RMK pathway upregulation effect on the striatum cellular density. Second, we will assess the effect of RAF1 mutations on brain development for the first time. Defining the relationships between the brain and Noonan's genetics will accelerate the use of genetic testing to inform prognosis and treatments in NS. Further, describing these relationships will provide critical data on the role of the RMK in brain development.