Abstract
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 β-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.
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Acknowledgements
We thank F. Francis for her helpful comments and critical readings of the manuscript, the subjects and their parents who contributed in this study and all the colleagues who provided clinical and imaging information. We thank R. Guerrini for providing us helpful advice. We are grateful to E. Leguern for allowing K.P. to develop this project and all the members of Cochin Institute genomic platform, Cochin Hospital Cell Bank, and Isabelle Souville for their technical assistance. This work was supported by funding from AP-HP, INSERM, FRM (funding within the frame of the Programme EQUIPEs FRM 2007) and ANR (ANR Neuro 2005, project A05183KS and ANR-06-NEURO-008-01 contract number RPV06055ASA). X.H.J. is supported by a PhD fellowship of the Ministère de l'Enseignement Supérieur et de la Recherche, by a grant for mobility from Université Paris Descartes and an EMBO short-term fellowship (ASTF 66.00-2008) for his work in NYU the Medical Center. K.P. is a post-doctoral researcher supported by FRM (Fondation pour la Recherche Medicale).
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J.C. coordinated and instigated the study with D.A.K. and J.F. X.H.J. performed biochemical, cellular and in vivo functional studies. N.B.-B., K.P. and C.F.-B. recruited cases and controls. N.B.-B., C.F.-B., S.O., P.L., M.K., I.S., G.P., P.P. and C.B. helped in collecting patients. K.P., D.A.K. and Y.S. screened the subject DNAs and performed the genetic analyses. L.C.-P. performed all DNA extractions from subject samples and coordinated interaction with clinicians. C.F.-B. performed the neuropathological analyses. G.T. and N.J.C. provided reagents and expertise for the biochemical study; X.P.K. helped compute and analyze the structures; C.C., E.B., P.B. and A.R. provided expertise and technical assistance for in utero RNAi analysis. F.P.-D.-T. and K.P. performed the RNA in situ hybridization analysis. X.H.J. and K.P. drafted the manuscript with the help of N.J.C. and J.C.
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Jaglin, X., Poirier, K., Saillour, Y. et al. Mutations in the β-tubulin gene TUBB2B result in asymmetrical polymicrogyria. Nat Genet 41, 746–752 (2009). https://doi.org/10.1038/ng.380
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DOI: https://doi.org/10.1038/ng.380
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