Mutations in α-Tubulin Cause Abnormal Neuronal Migration in Mice and Lissencephaly in Humans

David A. Keays, Guoling Tian, Karine Poirier, Guo Jen Huang, Christian Siebold, James Cleak, Peter L. Oliver, Martin Fray, Robert J. Harvey, Zoltán Molnár, Maria C. Piñon, Neil Dear, William Valdar, Steve D.M. Brown, Kay E. Davies, J. Nicholas P. Rawlins, Nicholas J. Cowan, Patrick Nolan, Jamel Chelly, Jonathan Flint*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

374 Scopus citations


The development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of α-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders.

Original languageEnglish
Pages (from-to)45-57
Number of pages13
Issue number1
StatePublished - 12 01 2007
Externally publishedYes


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