@article{71f3a6c45cd148ccb49652afdd5b06c5,
title = "Mutations in α-Tubulin Cause Abnormal Neuronal Migration in Mice and Lissencephaly in Humans",
abstract = "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.",
author = "Keays, \{David A.\} and Guoling Tian and Karine Poirier and Huang, \{Guo Jen\} and Christian Siebold and James Cleak and Oliver, \{Peter L.\} and Martin Fray and Harvey, \{Robert J.\} and Zolt{\'a}n Moln{\'a}r and Pi{\~n}on, \{Maria C.\} and Neil Dear and William Valdar and Brown, \{Steve D.M.\} and Davies, \{Kay E.\} and Rawlins, \{J. Nicholas P.\} and Cowan, \{Nicholas J.\} and Patrick Nolan and Jamel Chelly and Jonathan Flint",
note = "Funding Information: The authors wish to thank Richard Wade-Martins, Jan Fullerton, Polinka Hernandez-Pliego, Sian Polley, and Peter Burns for their assistance with experimental procedures. We are indebted to Fiona Francis and Sheila McCormick for critical reading of the manuscript. The authors are also grateful to the patients and their parents who contributed in this study, as well as to Sylvie Manouvrier, Doroth{\'e}e Ville, Isabelle Desguerre, Diana Rodroguez, and Ch{\'e}rif Beljord for providing clinical and imaging information. Thanks to Tom Jessell, Nenad {\v S}estan, and Richard Holt for help with antibodies. D.A.K. has been funded by the Christopher Welch Trust and is an OXION Training Fellow. J.F. is supported by the Wellcome Trust. N.J.C. acknowledges the support of a grant (R01 DK47234) from the NIH. The human elements of this study have been funded by ANR-05-NEUR-040-01. ",
year = "2007",
month = jan,
day = "12",
doi = "10.1016/j.cell.2006.12.017",
language = "English",
volume = "128",
pages = "45--57",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier B.V.",
number = "1",
}