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 journalArticle

Abstract

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
JournalCell
Volume140
Issue number1
DOIs
StatePublished - Jan 8 2010

Fingerprint

Kinesin
Tubulin
Microtubules
Mutation
Neuroimaging
Agenesis of Corpus Callosum
Oculomotor Nerve
Ocular Motility Disorders
Pyramidal Tracts
Mammals
Polyneuropathies
Facial Paralysis
Neurology
Missense Mutation
Nervous System Diseases
Yeast
Neurons
Cell Movement
Yeasts
Maintenance

Keywords

  • CELLBIO
  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Tischfield, M. A., Baris, H. N., Wu, C., Rudolph, G., Van Maldergem, L., He, W., ... Engle, E. C. (2010). Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance. Cell, 140(1), 74-87. https://doi.org/10.1016/j.cell.2009.12.011

Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance. / Tischfield, Max A.; Baris, Hagit N.; Wu, Chen; Rudolph, Guenther; Van Maldergem, Lionel; He, Wei; Chan, Wai Man; Andrews, Caroline; Demer, Joseph L.; Robertson, Richard L.; Mackey, David A.; Ruddle, Jonathan B.; Bird, Thomas D.; Gottlob, Irene; Pieh, Christina; Traboulsi, Elias I.; Pomeroy, Scott L.; Hunter, David G.; Soul, Janet S.; Newlin, Anna; Sabol, Louise J.; Doherty, Edward J.; de Uzcátegui, Clara E.; de Uzcátegui, Nicolas; Collins, Mary Louise Z; Sener, Emin C.; Wabbels, Bettina; Hellebrand, Heide; Meitinger, Thomas; de Berardinis, Teresa; Magli, Adriano; Schiavi, Costantino; Pastore-Trossello, Marco; Koc, Feray; Wong, Agnes M.; Levin, Alex V.; Geraghty, Michael T.; Descartes, Maria; Flaherty, Maree; Jamieson, Robyn V.; Møller, H. U.; Meuthen, Ingo; Callen, David F.; Kerwin, Janet; Lindsay, Susan; Meindl, Alfons; Gupta, Mohan L.; Pellman, David; Engle, Elizabeth C.

In: Cell, Vol. 140, No. 1, 08.01.2010, p. 74-87.

Research output: Contribution to journalArticle

Tischfield, MA, Baris, HN, Wu, C, Rudolph, G, Van Maldergem, L, He, W, Chan, WM, Andrews, C, Demer, JL, Robertson, RL, Mackey, DA, Ruddle, JB, Bird, TD, Gottlob, I, Pieh, C, Traboulsi, EI, Pomeroy, SL, Hunter, DG, Soul, JS, Newlin, A, Sabol, LJ, Doherty, EJ, de Uzcátegui, CE, de Uzcátegui, 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, Møller, HU, Meuthen, I, Callen, DF, Kerwin, J, Lindsay, S, Meindl, A, Gupta, ML, Pellman, D & Engle, EC 2010, 'Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance', Cell, vol. 140, no. 1, pp. 74-87. https://doi.org/10.1016/j.cell.2009.12.011
Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L, He W et al. Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance. Cell. 2010 Jan 8;140(1):74-87. https://doi.org/10.1016/j.cell.2009.12.011
Tischfield, Max A. ; Baris, Hagit N. ; Wu, Chen ; Rudolph, Guenther ; Van Maldergem, Lionel ; He, Wei ; Chan, Wai Man ; Andrews, Caroline ; Demer, Joseph L. ; Robertson, Richard L. ; Mackey, David A. ; Ruddle, Jonathan B. ; Bird, Thomas D. ; Gottlob, Irene ; Pieh, Christina ; Traboulsi, Elias I. ; Pomeroy, Scott L. ; Hunter, David G. ; Soul, Janet S. ; Newlin, Anna ; Sabol, Louise J. ; Doherty, Edward J. ; de Uzcátegui, Clara E. ; de Uzcátegui, Nicolas ; Collins, Mary Louise Z ; Sener, Emin C. ; Wabbels, Bettina ; Hellebrand, Heide ; Meitinger, Thomas ; de Berardinis, Teresa ; Magli, Adriano ; Schiavi, Costantino ; Pastore-Trossello, Marco ; Koc, Feray ; Wong, Agnes M. ; Levin, Alex V. ; Geraghty, Michael T. ; Descartes, Maria ; Flaherty, Maree ; Jamieson, Robyn V. ; Møller, H. U. ; Meuthen, Ingo ; Callen, David F. ; Kerwin, Janet ; Lindsay, Susan ; Meindl, Alfons ; Gupta, Mohan L. ; Pellman, David ; Engle, Elizabeth C. / Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance. In: Cell. 2010 ; Vol. 140, No. 1. pp. 74-87.
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AB - 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.

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