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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.

Original publication

DOI

10.1016/j.ajhg.2009.10.007

Type

Journal article

Journal

Am J Hum Genet

Publication Date

11/2009

Volume

85

Pages

737 - 744

Keywords

Base Sequence, Child, Child, Preschool, Consanguinity, Female, Gene Expression, Genes, Recessive, Genetic Variation, Humans, Male, Malformations of Cortical Development, Molecular Sequence Data, Mutation, Nuclear Family, Optic Nerve Diseases, Pakistan, Pedigree, Polymorphism, Single Nucleotide, Protein Isoforms, Syndrome, Tubulin