title: Mutations in alpha-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 alpha-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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Keays
authors.forename: Guoling
authors.initials: G
authors.lastname: Tian
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.forename: Guo-Jen
authors.initials: GJ
authors.lastname: Huang
authors.forename: Christian
authors.initials: C
authors.lastname: Siebold
authors.forename: James
authors.initials: J
authors.lastname: Cleak
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.forename: Martin
authors.initials: M
authors.lastname: Fray
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harvey
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Molnár
authors.forename: Maria C
authors.initials: MC
authors.lastname: Piñon
authors.forename: Neil
authors.initials: N
authors.lastname: Dear
authors.forename: William
authors.initials: W
authors.lastname: Valdar
authors.forename: Steve D M
authors.initials: SD
authors.lastname: Brown
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.forename: J Nicholas P
authors.initials: JN
authors.lastname: Rawlins
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cowan
authors.forename: Patrick
authors.initials: P
authors.lastname: Nolan
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000473:pathology; D001522:Behavior, Animal; D002465:Cell Movement; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D019281:Dimerization; D005260:Female; D018698:Glutamic Acid / Q000235:genetics; D006160:Guanosine Triphosphate / Q000378:metabolism; D006624:Hippocampus / Q000002:abnormalities* / Q000473:pathology; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000473:pathology*; D010641:Phenotype; D012694:Serine / Q000235:genetics; D014404:Tubulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014404:Tubulin; D018698:Glutamic Acid; D012694:Serine; D006160:Guanosine Triphosphate