Mechansims of Shroom2 function in development and disease



 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.