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Human TUBB3 mutations perturb microtubule dynamics, kinesin interations, and axon guidance


Tischfield, MA and Baris, HN and Wu, C and Rudolph, G and Van Maldergem, L and He, W and Chan, WM and Andrews, C and Demer, JL and Robertson, RL and Mackey, DA and Ruddle, JB and Bird, TD and Gottlob, I and Pieh, C and Traboulsi, EI and Pomeroy, SL and Hunter, DG and Soul, JS and Newlin, A and Sabol, LJ and Doherty, EJ and de Uzcategui, CE and de Uzcategui, N and Collins, MLZ and Sener, EC and Wabbels, B and Hellebrand, H and Meitinger, T and de Berardinis, T and Magli, A and Schiavi, C and Pastore-Trossello, M and Koc, F and Wong, AM and Levin, AV and Geraghty, MT and Descartes, M and Flaherty, M and Jamieson, RV and Moller, HU and Meuthen, I and Callen, DF and Kerwin, J and Lindsay, S and Meindl, A and Gupta, ML and Pellman, D and Engle, EC, Human TUBB3 mutations perturb microtubule dynamics, kinesin interations, and axon guidance, Cell, 140, (1) pp. 74-87. ISSN 0092-8674 (2010) [Refereed Article]

DOI: doi:10.1016/j.cell.2009.12.011


We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific β-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. © 2010 Elsevier Inc. All rights reserved.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Vision science
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Mackey, DA (Professor David Mackey)
ID Code:67880
Year Published:2010
Web of Science® Times Cited:384
Deposited By:Medicine
Deposited On:2011-03-08
Last Modified:2011-04-18

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