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 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.
authors.affiliation: Department of Neurology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Max A
authors.initials: MA
authors.lastname: Tischfield
authors.forename: Hagit N
authors.initials: HN
authors.lastname: Baris
authors.forename: Chen
authors.initials: C
authors.lastname: Wu
authors.forename: Guenther
authors.initials: G
authors.lastname: Rudolph
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.forename: Caroline
authors.initials: C
authors.lastname: Andrews
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Demer
authors.forename: Richard L
authors.initials: RL
authors.lastname: Robertson
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Ruddle
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: Irene
authors.initials: I
authors.lastname: Gottlob
authors.forename: Christina
authors.initials: C
authors.lastname: Pieh
authors.forename: Elias I
authors.initials: EI
authors.lastname: Traboulsi
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.forename: David G
authors.initials: DG
authors.lastname: Hunter
authors.forename: Janet S
authors.initials: JS
authors.lastname: Soul
authors.forename: Anna
authors.initials: A
authors.lastname: Newlin
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Sabol
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Doherty
authors.forename: Clara E
authors.initials: CE
authors.lastname: de Uzcátegui
authors.forename: Nicolas
authors.initials: N
authors.lastname: de Uzcátegui
authors.forename: Mary Louise Z
authors.initials: ML
authors.lastname: Collins
authors.forename: Emin C
authors.initials: EC
authors.lastname: Sener
authors.forename: Bettina
authors.initials: B
authors.lastname: Wabbels
authors.forename: Heide
authors.initials: H
authors.lastname: Hellebrand
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Teresa
authors.initials: T
authors.lastname: de Berardinis
authors.forename: Adriano
authors.initials: A
authors.lastname: Magli
authors.forename: Costantino
authors.initials: C
authors.lastname: Schiavi
authors.forename: Marco
authors.initials: M
authors.lastname: Pastore-Trossello
authors.forename: Feray
authors.initials: F
authors.lastname: Koc
authors.forename: Agnes M
authors.initials: AM
authors.lastname: Wong
authors.forename: Alex V
authors.initials: AV
authors.lastname: Levin
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
authors.forename: Maria
authors.initials: M
authors.lastname: Descartes
authors.forename: Maree
authors.initials: M
authors.lastname: Flaherty
authors.forename: Robyn V
authors.initials: RV
authors.lastname: Jamieson
authors.forename: H U
authors.initials: HU
authors.lastname: Møller
authors.forename: Ingo
authors.initials: I
authors.lastname: Meuthen
authors.forename: David F
authors.initials: DF
authors.lastname: Callen
authors.forename: Janet
authors.initials: J
authors.lastname: Kerwin
authors.forename: Susan
authors.initials: S
authors.lastname: Lindsay
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Mohan L
authors.initials: ML
authors.lastname: Gupta
authors.forename: David
authors.initials: D
authors.lastname: Pellman
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002470:Cell Survival; D002648:Child; D002658:Developmental Disabilities; D005260:Female; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D021381:Protein Transport; D014404:Tubulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C498585:TUBB3 protein, human; D014404:Tubulin; D016547:Kinesins