1. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance
- Author
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Ingo Meuthen, Janet Kerwin, Teresa de Berardinis, Alfons Meindl, Costantino Schiavi, Robyn V. Jamieson, Christina Pieh, Hagit N. Baris, Bettina Wabbels, Feray Koc, Wei He, Scott L. Pomeroy, Maree Flaherty, Joseph L. Demer, David A. Mackey, Emin Cumhur Sener, Jonathan B Ruddle, Lionel Van Maldergem, Louise J. Sabol, Susan Lindsay, Nicolas Uzcategui, Irene Gottlob, David F. Callen, Max A. Tischfield, Richard L. Robertson, Clara E. de Uzcategui, Thomas D. Bird, Janet S. Soul, Alex V. Levin, Marco Pastore-Trossello, Thomas Meitinger, Hans Ulrik Møller, Elizabeth C. Engle, Mary Louise Z. Collins, David G. Hunter, Maria Descartes, Edward J. Doherty, Mohan L. Gupta, Adriano Magli, Agnes M. F. Wong, Caroline Andrews, Chen Wu, Elias I. Traboulsi, Wai-Man Chan, Michael T. Geraghty, David Pellman, Anna Newlin, G. Rudolph, Heide Hellebrand, USA, M. A. TISCHFIELD, H. N. BARIS, C. WU, G. RUDOLPH, L. VAN MALDERGEM, W. HE, WAI-MAN CHAN, C. ANDREWS, J. L. DEMER, R. L. ROBERTSON, D. A. MACKEY, J. B. RUDDLE, T. D. BIRD, I. GOTTLOB, C. PIEH, E. TRABOULSI, S. POMEROY, D. HUNTER, J. S. SOUL, A. NEWLIN, L. J. SABOL, E. J. DOHERTY, C. E. DE UZCATEGUI, N. DE UZCATEGUI, M. L. Z. COLLINS, E. C. SENER, B. WABBELS, H. HELLEBRAND, T. MEITINGER, T. DE BERARDINIS, A. MAGLI, C. SCHIAVI, M. PASTORE-TROSSELLO, F. KOC, A. M. WONG, A. L. LEVIN, M. T. GERAGHTY, M. DESCARTES, M. FLAHERTY, R. V. JAMIESON, H. U. MOELLER, I. MEUTHEN, D. F. CALLEN, J. KERWIN, S. LINDSAY, A. MEINDLI, M.L. GUPTA Jr, D. PELLMAN, E. C. ENGLE, Acibadem University Dspace, 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, J, Newlin, A, Sabol, Lj, Doherty, Ej, de Uzcátegui, Ce, de Uzcátegui, N, Collins, Ml, Sener, Ec, Wabbels, B, Hellebrand, H, Meitinger, T, DE BERARDINIS, Teresa, Magli, Adriano, 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, Jr, Pellman, D, and Engle, E. C.
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Male ,Models, Molecular ,Nervous system ,Cell Survival ,Developmental Disabilities ,Molecular Sequence Data ,Mutation, Missense ,HUMDISEASE ,Kinesins ,Anterior commissure ,Biology ,medicine.disease_cause ,Microtubules ,MOLNEURO ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Tubulin ,Microtubule ,medicine ,Animals ,Humans ,Missense mutation ,Amino Acid Sequence ,Child ,Genetics ,Mutation ,Biochemistry, Genetics and Molecular Biology(all) ,Brain ,Axons ,extraocular muscles ,Mice, Inbred C57BL ,Protein Transport ,medicine.anatomical_structure ,biology.protein ,TUBB3 syndrome ,Kinesin ,Female ,CELLBIO ,Axon guidance ,CFEOM3 ,Neuroscience - Abstract
none 49 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. none M. A. TISCHFIELD; H. N. BARIS; C. WU; G. RUDOLPH; L. VAN MALDERGEM; W. HE; WAI-MAN CHAN; C. ANDREWS; J. L. DEMER; R. L. ROBERTSON; D. A. MACKEY; J. B. RUDDLE; T. D. BIRD; I. GOTTLOB; C. PIEH; E. TRABOULSI; S. POMEROY; D. HUNTER; J. S. SOUL; A. NEWLIN; L. J. SABOL; E. J. DOHERTY; C. E. DE UZCATEGUI; N. DE UZCATEGUI; M. L. Z. COLLINS; E. C. SENER; B. WABBELS; H. HELLEBRAND; T. MEITINGER; T. DE BERARDINIS; A. MAGLI; C. SCHIAVI; M. PASTORE-TROSSELLO; F. KOC; A. M. WONG; A. L. LEVIN; M. T. GERAGHTY; M. DESCARTES; M. FLAHERTY; R. V. JAMIESON; H. U. MOELLER; I. MEUTHEN; D. F. CALLEN; J. KERWIN; S. LINDSAY; A. MEINDLI; M.L. GUPTA Jr; D. PELLMAN; E. C. ENGLE M. A. TISCHFIELD; H. N. BARIS; C. WU; G. RUDOLPH; L. VAN MALDERGEM; W. HE; WAI-MAN CHAN; C. ANDREWS; J. L. DEMER; R. L. ROBERTSON; D. A. MACKEY; J. B. RUDDLE; T. D. BIRD; I. GOTTLOB; C. PIEH; E. TRABOULSI; S. POMEROY; D. HUNTER; J. S. SOUL; A. NEWLIN; L. J. SABOL; E. J. DOHERTY; C. E. DE UZCATEGUI; N. DE UZCATEGUI; M. L. Z. COLLINS; E. C. SENER; B. WABBELS; H. HELLEBRAND; T. MEITINGER; T. DE BERARDINIS; A. MAGLI; C. SCHIAVI; M. PASTORE-TROSSELLO; F. KOC; A. M. WONG; A. L. LEVIN; M. T. GERAGHTY; M. DESCARTES; M. FLAHERTY; R. V. JAMIESON; H. U. MOELLER; I. MEUTHEN; D. F. CALLEN; J. KERWIN; S. LINDSAY; A. MEINDLI; M.L. GUPTA Jr; D. PELLMAN; E. C. ENGLE
- Published
- 2010