Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance

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 NewlinLouise J. Sabol, Edward J. Doherty, Clara E. de Uzcátegui, Nicolas de Uzcátegui, 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, David Pellman, Elizabeth C. Engle

Research output: Contribution to journalArticlepeer-review

364 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)74-87
Number of pages14
Issue number1
StatePublished - Jan 8 2010
Externally publishedYes



ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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