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Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

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.

Pubmed ID: 20074521

Authors

  • 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 ML
  • 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

Journal

Cell

Publication Data

January 8, 2010

Associated Grants

  • Agency: NEI NIH HHS, Id: F32 EY016306
  • Agency: NEI NIH HHS, Id: F32 EY016306-01
  • Agency: Medical Research Council, Id: G9900837
  • Agency: NICHD NIH HHS, Id: HD18655
  • Agency: NICHD NIH HHS, Id: P30 HD018655
  • Agency: NICHD NIH HHS, Id: P30 HD018655-28
  • Agency: NEI NIH HHS, Id: R01 EY008313
  • Agency: NEI NIH HHS, Id: R01 EY008313-18
  • Agency: NEI NIH HHS, Id: R01 EY008313-19
  • Agency: NEI NIH HHS, Id: R01 EY012498
  • Agency: NEI NIH HHS, Id: R01 EY012498
  • Agency: NEI NIH HHS, Id: R01 EY012498-06
  • Agency: NEI NIH HHS, Id: R01 EY012498-07
  • Agency: NEI NIH HHS, Id: R01 EY012498-08
  • Agency: NEI NIH HHS, Id: R01 EY012498-09
  • Agency: NEI NIH HHS, Id: R01 EY012498-10
  • Agency: NEI NIH HHS, Id: R01 EY013583
  • Agency: NEI NIH HHS, Id: R01 EY013583
  • Agency: NEI NIH HHS, Id: R01 EY013583-06
  • Agency: NEI NIH HHS, Id: R01 EY013583-07
  • Agency: NEI NIH HHS, Id: R01 EY013583-08
  • Agency: NIGMS NIH HHS, Id: R01 GM061345
  • Agency: NIGMS NIH HHS, Id: R01 GM061345-08
  • Agency: NIGMS NIH HHS, Id: R01 GM061345-08
  • Agency: NEI NIH HHS, Id: T32 EY007143
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Axons
  • Brain
  • Cell Survival
  • Child
  • Developmental Disabilities
  • Female
  • Humans
  • Kinesin
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microtubules
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense
  • Protein Transport
  • Tubulin