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Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

ABSTRACT: We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.

SUBMITTER: Tischfield MA

PROVIDER: S-EPMC3164117 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

Tischfield Max A MA Baris Hagit N HN Wu Chen C Rudolph Guenther G Van Maldergem Lionel L He Wei W Chan Wai-Man WM Andrews Caroline C Demer Joseph L JL Robertson Richard L RL Mackey David A DA Ruddle Jonathan B JB Bird Thomas D TD Gottlob Irene I Pieh Christina C Traboulsi Elias I EI Pomeroy Scott L SL Hunter David G DG Soul Janet S JS Newlin Anna A Sabol Louise J LJ Doherty Edward J EJ de Uzcátegui Clara E CE de Uzcátegui Nicolas N Collins Mary Louise Z ML Sener Emin C EC Wabbels Bettina B Hellebrand Heide H Meitinger Thomas T de Berardinis Teresa T Magli Adriano A Schiavi Costantino C Pastore-Trossello Marco M Koc Feray F Wong Agnes M AM Levin Alex V AV Geraghty Michael T MT Descartes Maria M Flaherty Maree M Jamieson Robyn V RV Møller H U HU Meuthen Ingo I Callen David F DF Kerwin Janet J Lindsay Susan S Meindl Alfons A Gupta Mohan L ML Pellman David D Engle Elizabeth C EC

Cell 20100101 1

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerve ...[more]

PMID: 20074521

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Project description:Microtubules are dynamic cytoskeletal elements coordinating and supporting a variety of neuronal processes, including cell division, migration, polarity, intracellular trafficking, and signal transduction. Mutations in genes encoding tubulins and microtubule-associated proteins are known to cause neurodevelopmental and neurodegenerative disorders. Growing evidence suggests that altered microtubule dynamics may also underlie or contribute to neurodevelopmental disorders and neurodegeneration. We report that biallelic mutations in TBCD, encoding one of the five co-chaperones required for assembly and disassembly of the αβ-tubulin heterodimer, the structural unit of microtubules, cause a disease with neurodevelopmental and neurodegenerative features characterized by early-onset cortical atrophy, secondary hypomyelination, microcephaly, thin corpus callosum, developmental delay, intellectual disability, seizures, optic atrophy, and spastic quadriplegia. Molecular dynamics simulations predicted long-range and/or local structural perturbations associated with the disease-causing mutations. Biochemical analyses documented variably reduced levels of TBCD, indicating relative instability of mutant proteins, and defective β-tubulin binding in a subset of the tested mutants. Reduced or defective TBCD function resulted in decreased soluble α/β-tubulin levels and accelerated microtubule polymerization in fibroblasts from affected subjects, demonstrating an overall shift toward a more rapidly growing and stable microtubule population. These cells displayed an aberrant mitotic spindle with disorganized, tangle-shaped microtubules and reduced aster formation, which however did not alter appreciably the rate of cell proliferation. Our findings establish that defective TBCD function underlies a recognizable encephalopathy and drives accelerated microtubule polymerization and enhanced microtubule stability, underscoring an additional cause of altered microtubule dynamics with impact on neuronal function and survival in the developing brain.

Dataset Information

Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

Publications

Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

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