TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity.

ABSTRACT: The microtubule cytoskeleton supports diverse cellular morphogenesis and migration processes during brain development. Mutations in tubulin genes are associated with severe human brain malformations known as 'tubulinopathies'; however, it is not understood how molecular-level changes in microtubule subunits lead to brain malformations. In this study, we demonstrate that missense mutations affecting arginine at position 402 (R402) of TUBA1A α-tubulin selectively impair dynein motor activity and severely and dominantly disrupt cortical neuronal migration. TUBA1A is the most commonly affected tubulin gene in tubulinopathy patients, and mutations altering R402 account for 30% of all reported TUBA1A mutations. We show for the first time that ectopic expression of TUBA1A-R402C and TUBA1A-R402H p

SUBMITTER: Aiken J 

PROVIDER: S-EPMC6452179 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature