title: Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities.
abstract: The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5 is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5 (M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5 in embryonic neurogenesis and microcephaly.
authors.affiliation: Institute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Breuss
authors.forename: Julian Ik-Tsen
authors.initials: JI
authors.lastname: Heng
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.forename: Guoling
authors.initials: G
authors.lastname: Tian
authors.forename: Xavier Hubert
authors.initials: XH
authors.lastname: Jaglin
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Qu
authors.forename: Andreas
authors.initials: A
authors.lastname: Braun
authors.forename: Thomas
authors.initials: T
authors.lastname: Gstrein
authors.forename: Linh
authors.initials: L
authors.lastname: Ngo
authors.forename: Matilda
authors.initials: M
authors.lastname: Haas
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Moutard
authors.forename: Sandrine
authors.initials: S
authors.lastname: Passemard
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.forename: Yunli
authors.initials: Y
authors.lastname: Xie
authors.forename: Kathryn J H
authors.initials: KJ
authors.lastname: Robson
authors.forename: Deepa Selvi
authors.initials: DS
authors.lastname: Rani
authors.forename: Kumarasamy
authors.initials: K
authors.lastname: Thangaraj
authors.forename: Tim
authors.initials: T
authors.lastname: Clausen
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Nicholas Justin
authors.initials: NJ
authors.lastname: Cowan
authors.forename: David Anthony
authors.initials: DA
authors.lastname: Keays
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008831:Microcephaly / Q000196:embryology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis / Q000235:genetics; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D014404:Tubulin