@article{426f454ce3924b798d7fe95e479c2944,
title = "Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance",
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.",
keywords = "CELLBIO, HUMDISEASE, MOLNEURO",
author = "Tischfield, {Max A.} and Baris, {Hagit N.} and Chen Wu and Guenther Rudolph and {Van Maldergem}, Lionel and Wei He and Chan, {Wai Man} and Caroline Andrews and Demer, {Joseph L.} and Robertson, {Richard L.} and Mackey, {David A.} and Ruddle, {Jonathan B.} and Bird, {Thomas D.} and Irene Gottlob and Christina Pieh and Traboulsi, {Elias I.} and Pomeroy, {Scott L.} and Hunter, {David G.} and Soul, {Janet S.} and Anna Newlin and Sabol, {Louise J.} and Doherty, {Edward J.} and {de Uzc{\'a}tegui}, {Clara E.} and {de Uzc{\'a}tegui}, Nicolas and Collins, {Mary Louise Z.} and Sener, {Emin C.} and Bettina Wabbels and Heide Hellebrand and Thomas Meitinger and {de Berardinis}, Teresa and Adriano Magli and Costantino Schiavi and Marco Pastore-Trossello and Feray Koc and Wong, {Agnes M.} and Levin, {Alex V.} and Geraghty, {Michael T.} and Maria Descartes and Maree Flaherty and Jamieson, {Robyn V.} and M{\o}ller, {H. U.} and Ingo Meuthen and Callen, {David F.} and Janet Kerwin and Susan Lindsay and Alfons Meindl and Gupta, {Mohan L.} and David Pellman and Engle, {Elizabeth C.}",
note = "Funding Information: We thank the families for their participation; Michelle DeLisle and Carrie Wu for technical assistance and members of the Engle lab for their thoughtful comments; A. Nurten Akarsu, Peter Kang, Lisa S Kearns, James Hoekel, Marijean Miller, Marilyn Miller, Peter Roggenk{\"a}mper, and Sandra Staffieri for pedigree referrals and/or clinical exam data. This work was supported by NIH R01 EY012498, R01 EY013583, HD18655 (E.C.E.), F32 EY016306 (H.B.), R01 GM061345-08 (D.P.), and VA Research Funds (T.D.B.). E.C.E. and D.P. are investigators of the Howard Hughes Medical Institute. ",
year = "2010",
month = jan,
day = "8",
doi = "10.1016/j.cell.2009.12.011",
language = "English (US)",
volume = "140",
pages = "74--87",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",
}