Mechansims of Shroom2 function in development and disease

 描述（由申请人提供）：本提案的目标是了解Shroom2的功能，并确定人类SHROOM2突变导致患者神经系统疾病的机制。这项工作的基础是观察到未诊断疾病网络患者UDP_7490在SHROOM 2中存在突变，该突变与智力残疾，肢带肌无力，巴宾斯基征和延迟的粗大运动控制有关。引人注目的是，我们的合作者已经在第二名患者中发现了SHROOM 2与神经系统疾病之间的类似关联。这些患者中的这些表型是高度信息化的，因为：1）所有这些表型先前已经在负端定向微管马达转运机制缺陷的人或动物模型中观察到，以及2）我们先前对Shroom2的工作表明，这种知之甚少的蛋白质控制微管负端的组织和不同细胞类型中基于微管的转运。基于这些发现，我们提出了两个目标：1）我们将评估Shroom2功能丧失在模型动物中的作用，以及2）我们将使用Shroom2功能的定量测定和无偏蛋白质组学方法来确定SHROOM2中疾病相关突变的作用。总之，这些目标将为Shroom2的作用机制提供前所未有的分子见解，并将促进我们对人类以前未认识到的神经系统疾病的理解。

 DESCRIPTION (provided by applicant): The goal of this proposal is to understand the function of Shroom2 and to determine the mechanisms by which mutations in human SHROOM2 cause neurological disease in patients. The work is grounded by the observation that the Undiagnosed Disease Network Patient UDP_7490 has a mutation in SHROOM2 that associates with intellectual disability, limb-girdle muscle weakness, Babinsky sign, and delayed gross motor control. Strikingly, our collaborator has identified a similar association between SHROOM2 and neurological disease in a second patient. These phenotypes in these patients are highly informative because: 1) all of these phenotypes have been observed previously in humans or animal models with defects in the minus-end directed microtubule motor transport machinery, and 2) our prior work on Shroom2 suggests that this poorly understood protein controls the organization of microtubule minus- ends and microtubule-based transport in diverse cell types. On the basis of these findings, we propose two aims: 1) we will assess the effect of Shroom2 loss of function in model animals, and 2) we will use quantitative assays of Shroom2 function and unbiased proteomic approaches to determine the effect of disease associated mutations in SHROOM2. Together, these Aims will provide unprecedented molecular insights into the Shroom2 mechanism of action and will advance our understanding of a previously un-recognized neurological disorder in humans.