Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.
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.
Tischfield
Max A
MA
Department of Neurology, Children's Hospital Boston, Boston, MA 02115, USA.
Baris
Hagit N
HN
Wu
Chen
C
Rudolph
Guenther
G
Van Maldergem
Lionel
L
He
Wei
W
Chan
Wai-Man
WM
Andrews
Caroline
C
Demer
Joseph L
JL
Robertson
Richard L
RL
Mackey
David A
DA
Ruddle
Jonathan B
JB
Bird
Thomas D
TD
Gottlob
Irene
I
Pieh
Christina
C
Traboulsi
Elias I
EI
Pomeroy
Scott L
SL
Hunter
David G
DG
Soul
Janet S
JS
Newlin
Anna
A
Sabol
Louise J
LJ
Doherty
Edward J
EJ
de Uzcátegui
Clara E
CE
de Uzcátegui
Nicolas
N
Collins
Mary Louise Z
ML
Sener
Emin C
EC
Wabbels
Bettina
B
Hellebrand
Heide
H
Meitinger
Thomas
T
de Berardinis
Teresa
T
Magli
Adriano
A
Schiavi
Costantino
C
Pastore-Trossello
Marco
M
Koc
Feray
F
Wong
Agnes M
AM
Levin
Alex V
AV
Geraghty
Michael T
MT
Descartes
Maria
M
Flaherty
Maree
M
Jamieson
Robyn V
RV
Møller
H U
HU
Meuthen
Ingo
I
Callen
David F
DF
Kerwin
Janet
J
Lindsay
Susan
S
Meindl
Alfons
A
Gupta
Mohan L
ML
Pellman
David
D
Engle
Elizabeth C
EC
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*
C498585:TUBB3 protein, human; D014404:Tubulin; D016547:Kinesins