Article (Scientific journals)
Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.
Tischfield, Max A; Baris, Hagit N; Wu, Chen et al.
2010In Cell, 140 (1), p. 74-87
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Keywords :
Amino Acid Sequence; Animals; Axons/metabolism; Brain/embryology/metabolism; Cell Survival; Child; Developmental Disabilities; Female; Humans; Kinesin/metabolism; Male; Mice; Mice, Inbred C57BL; Microtubules/metabolism; Models, Molecular; Molecular Sequence Data; Mutation, Missense; Protein Transport; Tubulin/chemistry/genetics/metabolism
Abstract :
[en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Tischfield, Max A
Baris, Hagit N
Wu, Chen;  Howard Hughes Medical Institute
Rudolph, Guenther;  Ludwig-Maximilians-University > University Eye Hospital
VAN MALDERGEM, Lionel ;  Université de Liège - ULiège > Centre de génétique humaine
He, Wei
Chan, Wai-Man;  Howard Hughes Medical Institute
Andrews, Caroline;  Howard Hughes Medical Institute
Demer, Joseph L;  David Geffen Medical School at University of California
Robertson, Richard L
Mackey, David A;  University of Melbourne > Department of Ophthalmology > Centre for Eye Research Australia
Ruddle, Jonathan B;  University of Melbourne > Department of Ophthalmology > Centre for Eye Research Australia
Bird, Thomas D;  University of Washington School of Medicine
Gottlob, Irene;  University of Leicester
Pieh, Christina;  University of Freiburg > University Eye Hospital
Traboulsi, Elias I;  Cole Eye Institute, Cleveland Clinic
Pomeroy, Scott L
Hunter, David G;  Children’s Hospital Boston
Soul, Janet S
Newlin, Anna;  NorthShore University HealthSystem
Sabol, Louise J;  Geisinger Medical Institute
Doherty, Edward J
de Uzcategui, Clara E
de Uzcategui, 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
Moller, H. U.
Meuthen, Ingo
Callen, David F
Kerwin, Janet
Lindsay, Susan
Meindl, Alfons
Gupta, Mohan L Jr
Pellman, David
Engle, Elizabeth C
More authors (39 more) Less
Language :
English
Title :
Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.
Publication date :
2010
Journal title :
Cell
ISSN :
0092-8674
eISSN :
1097-4172
Publisher :
Cell Press, Cambridge, United States - Massachusetts
Volume :
140
Issue :
1
Pages :
74-87
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 22 February 2012

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