title: Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.
abstract: The critical importance of cytoskeletal function for correct neuronal migration during development of the cerebral cortex has been underscored by the identities of germline mutations underlying a number of human neurodevelopmental disorders. The proteins affected include TUBA1A, a major alpha-tubulin isoform, and microtubule-associated components such as doublecortin, and LIS1. Mutations in these genes are associated with the anatomical abnormality lissencephaly, which is believed to reflect failure of neuronal migration. An important recent observation has been the dependence of cortical neuronal migration upon acetylation of alpha-tubulin at lysine 40 by the histone acetyltransferase Elongator complex. Here, we describe a recognizable autosomal recessive syndrome, characterized by generalized polymicrogyria in association with optic nerve hypoplasia (PMGOH). By autozygosity mapping, we show that the molecular basis for this condition is mutation of the TUBA8 gene, encoding a variant alpha-tubulin of unknown function that is not susceptible to the lysine 40 acetylation that regulates microtubule function during cortical neuron migration. Together with the unique expression pattern of TUBA8 within the developing cerebral cortex, these observations suggest a role for this atypical microtubule component in regulating mammalian brain development.
authors.affiliation: Section of Genetics (Leeds Institute of Molecular Medicine [LIMM]), Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Abdollahi
authors.forename: Ewan
authors.initials: E
authors.lastname: Morrison
authors.forename: Tamara
authors.initials: T
authors.lastname: Sirey
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Molnar
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Hayward
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.forename: Kelly
authors.initials: K
authors.lastname: Springell
authors.forename: C Geoff
authors.initials: CG
authors.lastname: Woods
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmed
authors.forename: Louise
authors.initials: L
authors.lastname: Hattingh
authors.forename: Peter
authors.initials: P
authors.lastname: Corry
authors.forename: Daniela T
authors.initials: DT
authors.lastname: Pilz
authors.forename: Neil
authors.initials: N
authors.lastname: Stoodley
authors.forename: Yanick
authors.initials: Y
authors.lastname: Crow
authors.forename: Graham R
authors.initials: GR
authors.lastname: Taylor
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
mesh_terms: D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D014644:Genetic Variation; D006801:Humans; D008297:Male; D054220:Malformations of Cortical Development / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D009679:Nuclear Family; D009901:Optic Nerve Diseases / Q000235:genetics* / Q000473:pathology; D010154:Pakistan; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D011859:Radiography; D013577:Syndrome; D014404:Tubulin / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; C408046:TUBA8 protein, human; D014404:Tubulin