Mechansims of Shroom2 function in development and disease

 描述(申请人提供)：这项建议的目标是了解Shroom2的功能，并确定人类SHROOM2突变导致患者神经疾病的机制。这项工作的基础是观察到，未诊断的疾病网络患者UDP_7490有SHROOM2突变，该突变与智力残疾、四肢腰带肌肉无力、巴宾斯基征和粗大运动控制延迟有关。令人惊讶的是，我们的合作者在第二个患者中发现了SHROOM2和神经疾病之间的类似关联。这些患者的这些表型具有很高的信息量，因为：1)所有这些表型以前在具有负端定向微管运动运输机制缺陷的人类或动物模型中被观察到，以及2)我们先前在Shroom2上的工作表明，这个鲜为人知的蛋白质控制着不同细胞类型中微管负端和基于微管的运输的组织。在这些发现的基础上，我们提出了两个目标：1)我们将评估Shroom2功能丧失对模型动物的影响，2)我们将使用Shroom2功能的定量分析和无偏倚的蛋白质组方法来确定SHROOM2疾病相关突变的影响。总之，这些目标将为Shroom2的作用机制提供前所未有的分子洞察力，并将促进我们对一种以前未被认识到的人类神经疾病的理解。

 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.