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Tischfield, M.A.* ; Baris, H.N.* ; Wu, C.* ; Rudolph, G.* ; van Maldergem, L.* ; He, W.* ; Chan, W.M.* ; Andrews, C.* ; Demer, J.L.* ; Robertson, R.L.* ; Mackey, D.A.* ; Ruddle, J.B.* ; Bird, T.D.* ; Gottlob, I.* ; Pieh, C.* ; Traboulsi, E.I.* ; Pomeroy, S.L.* ; Hunter, D.G.* ; Soul, J.S.* ; Newlin, A.* ; Sabol, L.J.* ; Doherty, E.J.* ; de Uzcátegui, C.E.* ; de Uzcátegui, N.* ; Collins, M.L.Z.* ; Sener, E.C.* ; Wabbels, B.* ; Hellebrand, H.* ; Meitinger, T. ; de Berardinis, T.* ; Magli, A.* ; Schiavi, C.* ; Pastore-Trossello, M.* ; Koc, F.* ; Wong, A.M.* ; Levin, A.V.* ; Geraghty, M.T.* ; Descartes, M.* ; Flaherty, M.* ; Jamieson, R.V.* ; Møller, H.U.* ; Meuthen, I.* ; Callen, D.F.* ; Kerwin, J.* ; Lindsay, S.* ; Meindl, A.* ; Gupta, M.L.* ; Pellman, D.* ; Engle, E.C.*

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

Cell 140, 74-87 (2010)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Beta-tubulin gene; Congential fibrosis; Extraocular-muscles; Mitotic spindle; Alpha-tubulin; In-vitro; Isotype; KIF21A; Yeast; Identification
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 140, Issue: 1, Pages: 74-87 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)