Mutation of the Variant α-Tubulin TUBA8 Results in Polymicrogyria with Optic Nerve Hypoplasia

• Published in: American journal of human genetics Vol. 85; no. 5; pp. 737 - 744
• Main Authors: Abdollahi, Mohammad R., Morrison, Ewan, Sirey, Tamara, Molnar, Zoltan, Hayward, Bruce E., Carr, Ian M., Springell, Kelly, Woods, C. Geoff, Ahmed, Mushtaq, Hattingh, Louise, Corry, Peter, Pilz, Daniela T., Stoodley, Neil, Crow, Yanick, Taylor, Graham R., Bonthron, David T., Sheridan, Eamonn
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 13.11.2009; Cell Press; Elsevier
• Subjects: Base Sequence; Biological and medical sciences; Child; Child, Preschool; Consanguinity; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; General aspects. Genetic counseling; Genes, Recessive; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Humans; Male; Malformations of Cortical Development - diagnostic imaging; Malformations of Cortical Development - genetics; Malformations of Cortical Development - pathology; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Nuclear Family; Optic Nerve Diseases - genetics; Optic Nerve Diseases - pathology; Pakistan; Pedigree; Polymorphism, Single Nucleotide; Protein Isoforms - genetics; Radiography; Syndrome; Tubulin - genetics; Human; Hypoplasia; Variant; Optic nerve; Tubulin; Malformation; Polymicrogyria; Genetics; Mutation
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2009.10.007

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 α-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 α-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 α-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.