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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.

Original publication

DOI

10.1038/ng.380

Type

Journal article

Journal

Nat Genet

Publication Date

06/2009

Volume

41

Pages

746 - 752

Keywords

Adolescent, Adult, Amino Acid Substitution, Cerebral Cortex, Child, Preschool, Female, Fetal Diseases, Genetic Variation, Humans, Lissencephaly, Malformations of Cortical Development, Mutation, Pia Mater, Pregnancy, Tubulin