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

获得见解：RMK 功能获得性突变对大脑发育和神经发育障碍的影响

基本信息

批准号：
10420859
负责人：
Tamar Green
金额：
$ 54.48万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-21 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10420859
关键词：
16 year old Address Affect Animal Model Anisotropy Area Attention Attention deficit hyperactivity disorder Biological Models Biology Brain Brain imaging Brain region Caenorhabditis elegans Child Child Psychiatry Complex Copy Number Polymorphism Corpus striatum structure Correlation Studies Data Development Disease Genes Genetic Genetic Diseases Genomics Human In Vitro Individual Investigation Learning Disabilities Location Maps Measures Methods Mitogen-Activated Protein Kinases Modality Modeling Molecular Molecular Genetics Mutation Myelin Neurodevelopmental Disorder Noonan Syndrome Outcome PTPN11 gene Pathogenicity Pathway interactions Penetrance Phenotype Phosphorylation Prognosis Proteins Psychological Tests RAF1 gene Rest Restriction Spectrum Imaging Risk Role Sampling Seeds Severities Signal Transduction Structure Surface Symptoms Syndrome System Testing Thick Time Translating Up-Regulation Variant Work autism spectrum disorder autosomal dominant mutation base brain tissue clinical application computational neuroscience connectome connectome based predictive modeling density gain of function gain of function mutation genetic risk factor genetic testing genetic variant human model human morbidity imaging modality imaging study in silico in vivo innovation insight interest molecular dynamics neuroimaging non-invasive imaging rare genetic disorder src Homology Region 2 Domain white matter

项目摘要

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.

项目概要/摘要罕见的遗传性疾病是人类发病的主要原因，经常影响大脑发育并导致神经发育障碍。在这里，我们建议使用努南综合症（NS，1：2000）作为人体模型系统提供有关 Ras/丝裂原激活蛋白激酶 (RMK) 遗传改变影响的关键数据关于人脑复杂的系统级生物学。三线证据支持将 NS 用作人类模型系统：1）NS是由特定基因高外显率的常染色体显性突变引起的与共同变异的特发性神经发育障碍遗传学相比，2) NS 的影响更大对大脑发育的影响，因此比特发性神经发育障碍的影响更大，3) NS 是与神经发育障碍（例如注意力能力、学习能力）风险增加相关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，特别是额纹状体连接。不过，数量有限关于其他 NS 突变 RAF1 和 SOS1 对发育中大脑的影响的现有数据。为了解决这个问题限制，我们建议确定三个主要的 NS 疾病基因 RAF1、PTPN11 和 SOS1 突变与纹状体改变的严重程度相关。提供关键数据 PTPN11遗传变异与大脑发育之间的关系，我们将测试PTPN11是否致病变异与大脑发育改变有关。最后，我们将测试是否全脑连接性可以预测 NS 的注意力能力。该目标将为注意力能力提供神经标记（特别是抑制）NS。我们将进行“深度表型分析”——纹状体的成像研究（体积、细胞密度、基于种子的功能连接）和全脑（表面积、皮质厚度、白质、皮质髓磷脂内容和全脑功能连接）并评估儿童（7-16 岁）的注意力（抑制）年龄）与 RAF1 (n=30)、PTPN11 (n=45) 和 SOS1 (n=30) 突变，并将它们与典型情况进行比较制定控制措施（n=45）。拟议工作的两个创新方面是使用限制谱成像（RSI）来绘制 RMK 通路上调对纹状体细胞密度的影响。其次，我们将首次评估 RAF1 突变对大脑发育的影响。定义大脑和努南遗传学之间的关系将加速基因测试的应用为 NS 的预后和治疗提供信息。此外，描述这些关系将提供关于 RMK 在大脑发育中的作用。