Overlapping cortical malformations and mutations in TUBB2B and TUBA1A
Open Access
- 29 January 2013
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 136 (2), 536-548
- https://doi.org/10.1093/brain/aws338
Abstract
Polymicrogyria and lissencephaly are causally heterogeneous disorders of cortical brain development, with distinct neuropathological and neuroimaging patterns. They can be associated with additional structural cerebral anomalies, and recurrent phenotypic patterns have led to identification of recognizable syndromes. The lissencephalies are usually single-gene disorders affecting neuronal migration during cerebral cortical development. Polymicrogyria has been associated with genetic and environmental causes and is considered a malformation secondary to abnormal post-migrational development. However, the aetiology in many individuals with these cortical malformations is still unknown. During the past few years, mutations in a number of neuron-specific α- and β-tubulin genes have been identified in both lissencephaly and polymicrogyria, usually associated with additional cerebral anomalies including callosal hypoplasia or agenesis, abnormal basal ganglia and cerebellar hypoplasia. The tubulin proteins form heterodimers that incorporate into microtubules, cytoskeletal structures essential for cell motility and function. In this study, we sequenced the TUBB2B and TUBA1A coding regions in 47 patients with a diagnosis of polymicrogyria and five with an atypical lissencephaly on neuroimaging. We identified four β-tubulin and two α-tubulin mutations in patients with a spectrum of cortical and extra-cortical anomalies. Dysmorphic basal ganglia with an abnormal internal capsule were the most consistent feature. One of the patients with a TUBB2B mutation had a lissencephalic phenotype, similar to that previously associated with a TUBA1A mutation. The remainder had a polymicrogyria-like cortical dysplasia, but the grey matter malformation was not typical of that seen in ‘classical’ polymicrogyria. We propose that the cortical malformations associated with these genes represent a recognizable tubulinopathy-associated spectrum that ranges from lissencephalic to polymicrogyric cortical dysplasias, suggesting shared pathogenic mechanisms in terms of microtubular function and interaction with microtubule-associated proteins.Keywords
This publication has 42 references indexed in Scilit:
- A developmental and genetic classification for malformations of cortical development: update 2012Brain, 2012
- Mutation of the Variant α-Tubulin TUBA8 Results in Polymicrogyria with Optic Nerve HypoplasiaAmerican Journal of Human Genetics, 2009
- Neuropathological phenotype of a distinct form of lissencephaly associated with mutations in TUBA1ABrain, 2008
- Refinement of cortical dysgeneses spectrum associated with TUBA1A mutationsJournal of Medical Genetics, 2008
- Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesisNature Genetics, 2007
- Trekking across the Brain: The Journey of Neuronal MigrationCell, 2007
- Homozygous Nonsense Mutations in KIAA1279 Are Associated with Malformations of the Central and Enteric Nervous SystemsAmerican Journal of Human Genetics, 2005
- Pax6, Tbr2, and Tbr1 Are Expressed Sequentially by Radial Glia, Intermediate Progenitor Cells, and Postmitotic Neurons in Developing NeocortexJournal of Neuroscience, 2005
- Protein–Protein interactions, cytoskeletal regulation and neuronal migrationNature Reviews Neuroscience, 2001
- MICROTUBULE POLYMERIZATION DYNAMICSAnnual Review of Cell and Developmental Biology, 1997