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

doi:10.1016/j.cell.2006.12.017

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 journal › Journal Article › peer-review

386 Scopus citations

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.

Original language	English
Pages (from-to)	45-57
Number of pages	13
Journal	Cell
Volume	128
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2006.12.017
State	Published - 12 01 2007
Externally published	Yes

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Keays, D. A., Tian, G., Poirier, K., Huang, G. J., Siebold, C., Cleak, J., Oliver, P. L., Fray, M., Harvey, R. J., Molnár, Z., Piñon, M. C., Dear, N., Valdar, W., Brown, S. D. M., Davies, K. E., Rawlins, J. N. P., Cowan, N. J., Nolan, P., Chelly, J., & Flint, J. (2007). Mutations in α-Tubulin Cause Abnormal Neuronal Migration in Mice and Lissencephaly in Humans. Cell, 128(1), 45-57. https://doi.org/10.1016/j.cell.2006.12.017

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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",

year = "2007",

month = jan,

day = "12",

doi = "10.1016/j.cell.2006.12.017",

language = "英语",

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Keays, DA, Tian, G, Poirier, K, Huang, GJ, Siebold, C, Cleak, J, Oliver, PL, Fray, M, Harvey, RJ, Molnár, Z, Piñon, MC, Dear, N, Valdar, W, Brown, SDM, Davies, KE, Rawlins, JNP, Cowan, NJ, Nolan, P, Chelly, J & Flint, J 2007, 'Mutations in α-Tubulin Cause Abnormal Neuronal Migration in Mice and Lissencephaly in Humans', Cell, vol. 128, no. 1, pp. 45-57. https://doi.org/10.1016/j.cell.2006.12.017

TY - JOUR

T1 - Mutations in α-Tubulin Cause Abnormal Neuronal Migration in Mice and Lissencephaly in Humans

AU - Keays, David A.

AU - Tian, Guoling

AU - Poirier, Karine

AU - Huang, Guo Jen

AU - Siebold, Christian

AU - Cleak, James

AU - Oliver, Peter L.

AU - Fray, Martin

AU - Harvey, Robert J.

AU - Molnár, Zoltán

AU - Piñon, Maria C.

AU - Dear, Neil

AU - Valdar, William

AU - Brown, Steve D.M.

AU - Davies, Kay E.

AU - Rawlins, J. Nicholas P.

AU - Cowan, Nicholas J.

AU - Nolan, Patrick

AU - Chelly, Jamel

AU - Flint, Jonathan

PY - 2007/1/12

Y1 - 2007/1/12

N2 - 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.

AB - 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.

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SN - 0092-8674

VL - 128

SP - 45

EP - 57

JO - Cell

JF - Cell

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ER -

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

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