Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria.
Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also polymicrogyria malformations.
Jaglin
Xavier Hubert
XH
Institut Cochin, Université Paris Descartes CNRS (UMR 8104), Paris, France.
Poirier
Karine
K
Saillour
Yoann
Y
Buhler
Emmanuelle
E
Tian
Guoling
G
Bahi-Buisson
Nadia
N
Fallet-Bianco
Catherine
C
Phan-Dinh-Tuy
Françoise
F
Kong
Xiang Peng
XP
Bomont
Pascale
P
Castelnau-Ptakhine
Laëtitia
L
Odent
Sylvie
S
Loget
Philippe
P
Kossorotoff
Manoelle
M
Snoeck
Irina
I
Plessis
Ghislaine
G
Parent
Philippe
P
Beldjord
Cherif
C
Cardoso
Carlos
C
Represa
Alfonso
A
Flint
Jonathan
J
Keays
David Anthony
DA
Cowan
Nicholas Justin
NJ
Chelly
Jamel
J
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology; D002675:Child, Preschool; D005260:Female; D005315:Fetal Diseases / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D054082:Lissencephaly / Q000235:genetics; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010841:Pia Mater / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D011247:Pregnancy; D014404:Tubulin / Q000235:genetics*
C576987:TUBB2B protein, human; D014404:Tubulin