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https://hdl.handle.net/2440/62221
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Type: | Journal article |
Title: | Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance |
Author: | Tischfield, M. Baris, H. Wu, C. Rudolph, G. van Maldergem, L. He, W. Chan, W. Andrews, C. Demer, J. Robertson, R. Mackey, D. Ruddle, J. Bird, T. Gottlob, I. Pieh, C. Traboulsi, E. Pomeroy, S. Hunter, D. Soul, J. Newlin, A. et al. |
Citation: | Cell, 2010; 140(1):74-87 |
Publisher: | Cell Press |
Issue Date: | 2010 |
ISSN: | 0092-8674 1097-4172 |
Statement of Responsibility: | Max A. Tischfield, Hagit N. Baris, Chen Wu, Guenther Rudolph, Lionel Van Maldergem, Wei He, Wai-Man Chan, Caroline Andrews, Joseph L. Demer, Richard L. Robertson, David A. Mackey, Jonathan B. Ruddle, Thomas D. Bird, Irene Gottlob, Christina Pieh, Elias I. Traboulsi, Scott L. Pomeroy, David G. Hunter, Janet S. Soul, Anna Newlin, Louise J. Sabol, Edward J. Doherty, Clara E. de Uzca´ tegui, Nicolas de Uzca´ tegui, Mary Louise Z. Collins, Emin C. Sener, Bettina Wabbels, Heide Hellebrand, Thomas Meitinger, Teresa de Berardinis, Adriano Magli, Costantino Schiavi, Marco Pastore-Trossello, Feray Koc, Agnes M. Wong, Alex V. Levin, Michael T. Geraghty, Maria Descartes, Maree Flaherty, Robyn V. Jamieson, H.U. Møller, Ingo Meuthen, David F. Callen, Janet Kerwin, Susan Lindsay, Alfons Meindl, Mohan L. Gupta, Jr., David Pellman, and Elizabeth C. Engle |
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. |
Keywords: | Brain Axons Microtubules Animals Mice, Inbred C57BL Humans Mice Tubulin Developmental Disabilities Cell Survival Amino Acid Sequence Protein Transport Mutation, Missense Models, Molecular Molecular Sequence Data Child Female Male Kinesins |
DOI: | 10.1016/j.cell.2009.12.011 |
Published version: | http://dx.doi.org/10.1016/j.cell.2009.12.011 |
Appears in Collections: | Aurora harvest 5 Medicine publications |
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