title: A mutation in Tubb2b, a human polymicrogyria gene, leads to lethality and abnormal cortical development in the mouse.
abstract: Human cortical malformations, including lissencephaly, polymicrogyria and other diseases of neurodevelopment, have been associated with mutations in microtubule subunits and microtubule-associated proteins. Here we report our cloning of the brain dimple (brdp) mouse mutation, which we recovered from an ENU screen for recessive perinatal phenotypes affecting neurodevelopment. We identify the causal mutation in the tubulin, beta-2b (Tubb2b) gene as a missense mutation at a highly conserved residue (N247S). Brdp/brdp homozygous mutants have significant thinning of the cortical epithelium, which is markedly more severe in the caudo-lateral portion of the telencephalon, and do not survive past birth. The cortical defects are largely due to a major increase in apoptosis and we note abnormal proliferation of the basal progenitors. Adult brdp/+ mice are viable and fertile but exhibit behavioral phenotypes. This allele of Tubb2b represents the most severely affected mouse tubulin phenotype reported to date and this is the first report of a tubulin mutation affecting neuronal proliferation and survival.
authors.affiliation: Present address: Divisions of Human Genetics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Stottmann
authors.forename: M
authors.initials: M
authors.lastname: Donlin
authors.forename: A
authors.initials: A
authors.lastname: Hafner
authors.forename: A
authors.initials: A
authors.lastname: Bernard
authors.forename: D A
authors.initials: DA
authors.lastname: Sinclair
authors.forename: D R
authors.initials: DR
authors.lastname: Beier
mesh_terms: D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D005260:Female; D005804:Genes, Lethal; D006801:Humans; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D009474:Neurons / Q000502:physiology; D010641:Phenotype; D011487:Protein Conformation; D016415:Sequence Alignment; D014404:Tubulin / Q000737:chemistry / Q000235:genetics*
chemical_list: C576987:TUBB2B protein, human; D014404:Tubulin