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Human TUBB3 mutations perturb microtubule dynamics, kinesin interations, and axon guidance
journal contribution
posted on 2023-05-17, 05:06 authored by Tischfield, MA, Baris, HN, Wu, C, Rudolph, G, Van Maldergem, L, He, W, Chan, WM, Andrews, C, Demer, JL, Robertson, RL, David MackeyDavid Mackey, Ruddle, JB, Bird, TD, Gottlob, I, Pieh, C, Traboulsi, EI, Pomeroy, SL, Hunter, DG, Soul, JS, Newlin, A, Sabol, LJ, Doherty, EJ, de Uzcategui, CE, de Uzcategui, N, Collins, MLZ, Sener, EC, Wabbels, B, Hellebrand, H, Meitinger, T, de Berardinis, T, Magli, A, Schiavi, C, Pastore-Trossello, M, Koc, F, Wong, AM, Levin, AV, Geraghty, MT, Descartes, M, Flaherty, M, Jamieson, RV, Moller, HU, Meuthen, I, Callen, DF, Kerwin, J, Lindsay, S, Meindl, A, Gupta, ML, Pellman, D, Engle, ECWe 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.
History
Publication title
CellVolume
140Pagination
74-87ISSN
0092-8674Department/School
Tasmanian School of MedicinePublisher
Cell PressPlace of publication
1100 Massachusetts Ave, Cambridge, USA, Ma, 02138Repository Status
- Restricted