Journal
CELL
Volume 128, Issue 1, Pages 45-57Publisher
CELL PRESS
DOI: 10.1016/j.cell.2006.12.017
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Funding
- Medical Research Council [MC_U142684172, MC_U142684175, MC_UP_1502/1, MC_U137761449, MC_U142684173, G0300200] Funding Source: researchfish
- Medical Research Council [G0300200, MC_U142684173, MC_U142684175, MC_UP_1502/1, MC_U137761449, MC_U142684172] Funding Source: Medline
- NIDDK NIH HHS [R01 DK047234, R01 DK47234] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
- MRC [MC_U137761449, MC_U142684173, MC_U142684175, MC_U142684172, G0300200, MC_UP_1502/1] Funding Source: UKRI
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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 alpha-1 tubulin (Tuba 1) 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 cle novo mutations in TUBA3, the human homolog of Tubal. 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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