ArticleHuman molecular genetics2019
TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed, 51 citations in OpenAlex.
- Tubulin autoregulation mediator TTC5 regulates neuronal morphology and migration.bioRxiv : the preprint server for biology · 2026Article
- Architects of the Developing Brain: Cytoskeleton-Organizing Molecules in Neurodevelopmental Disorders.Cells · 2026Review
- A Covalent and Modulable Inhibitor of the Tubulin-Microtubule System: Insights Into the Mechanism of Cacalol.Chemical biology & drug design · 2025Article
- Understanding the Molecular Basis of Miller-Dieker Syndrome.International journal of molecular sciences · 2025Review
- Spatiotemporal modeling reveals high-resolution invasion states in glioblastoma.Genome biology · 2024Article
- Spastin locally amplifies microtubule dynamics to pattern the axon for presynaptic cargo delivery.Current biology : CB · 2024Article
- A stable microtubule bundle formed through an orchestrated multistep process controls quiescence exit.eLife · 2024Article
- Lissencephaly caused by aFrontiers in pediatrics · 2024Article
- Deciphering the Tubulin Language: Molecular Determinants and Readout Mechanisms of the Tubulin Code in Neurons.International journal of molecular sciences · 2023Review
- The tubulin database: Linking mutations, modifications, ligands and local interactions.PloS one · 2023Article
- MAPping tubulin mutations.Frontiers in cell and developmental biology · 2023Review
- Case report: Structural brain abnormalities inFrontiers in pediatrics · 2023Article
- Selective motor activation in organelle transport along axons.Nature reviews. Molecular cell biology · 2022Review
- Article
- Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies.European journal of human genetics : EJHG · 2022Article
- The molecular biology of tubulinopathies: Understanding the impact of variants on tubulin structure and microtubule regulation.Frontiers in cellular neuroscience · 2022Review
- Microtubules in Microorganisms: How Tubulin Isotypes Contribute to Diverse Cytoskeletal Functions.Frontiers in cell and developmental biology · 2022Review
- Tubulin isotypes optimize distinct spindle positioning mechanisms during yeast mitosis.The Journal of cell biology · 2021Article
- Modeling spatiotemporally varying protein-protein interactions in CyLaKS, the Cytoskeleton Lattice-based Kinetic Simulator.The European physical journal. E, Soft matter · 2021Article
- [Effect of dexamethasone on the expression of Dynein heavy chain and Dynactin in the cytoplasm of fetal rat cerebral cortical neurons culturedZhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2021Article
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3 authors at 1 institution in 1 country.
Funding
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 patient alleles is sufficient to dominantly disrupt cortical neuronal migration in the developing mouse brain, strongly supporting a causal role in the pathology of brain malformation. To isolate the precise molecular impact of R402 mutations, we generated analogous R402C and R402H mutations in budding yeast α-tubulin, which exhibit a simplified microtubule cytoskeleton. We find that R402 mutant tubulins assemble into microtubules that support normal kinesin motor activity but fail to support the activity of dynein motors. Importantly, the level of dynein impairment scales with the expression level of the mutant in the cell, suggesting a 'poisoning' mechanism in which R402 mutant α-tubulin acts dominantly by populating microtubules with defective binding sites for dynein. Based on our results, we propose a new model for the molecular pathology of tubulinopathies that may also extend to other tubulin-related neuropathies.
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