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.

Public Health Relevance

This study centers on the Shroom2 protein, which remains very poorly defined, yet is associated with neurological disease in human patients. We propose to use a battery of animal model experiments and unbiased screening for Shroom2 interacting proteins to elucidate the mechanisms by which Shroom2 controls development and function of the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21GM119021-02
Application #
9271210
Study Section
Special Emphasis Panel (ZHG1)
Program Officer
Krasnewich, Donna M
Project Start
2016-05-09
Project End
2018-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759
Akhmetov, Azat; Laurent, Jon M; Gollihar, Jimmy et al. (2018) Single-step Precision Genome Editing in Yeast Using CRISPR-Cas9. Bio Protoc 8:
Akhmetov, Azat; Ellington, Andrew D; Marcotte, Edward M (2018) A highly parallel strategy for storage of digital information in living cells. BMC Biotechnol 18:64
Verbeke, Eric J; Mallam, Anna L; Drew, Kevin et al. (2018) Classification of Single Particles from Human Cell Extract Reveals Distinct Structures. Cell Rep 24:259-268.e3
Kachroo, Aashiq H; Laurent, Jon M; Akhmetov, Azat et al. (2017) Systematic bacterialization of yeast genes identifies a near-universally swappable pathway. Elife 6:
Drew, Kevin; Lee, Chanjae; Huizar, Ryan L et al. (2017) Integration of over 9,000 mass spectrometry experiments builds a global map of human protein complexes. Mol Syst Biol 13:932
Session, Adam M; Uno, Yoshinobu; Kwon, Taejoon et al. (2016) Genome evolution in the allotetraploid frog Xenopus laevis. Nature 538:336-343