Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria.

Nat Genet 2009 Jun 24;41(6):746-52. Epub 2009 May 24.

Institut Cochin, Université Paris Descartes CNRS (UMR 8104), Paris, France.

Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also polymicrogyria malformations.

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883584PMC
June 2009

Publication Analysis

Top Keywords

gene tubb2b
8
neuronal migration
8
beta-tubulin gene
8
asymmetrical polymicrogyria
8
mutations beta-tubulin
8
fetus bilateral
4
tubb2b required
4
bilateral asymmetrical
4
27-gestational-week fetus
4
demonstrates tubb2b
4
neuropathological examination
4
inactivation demonstrates
4
polymicrogyria neuropathological
4
required neuronal
4
individuals 27-gestational-week
4
novo mutations
4
report novo
4
lamination report
4
disease-associated mutations
4
migration disease-associated
4

Similar Publications

Overlapping cortical malformations and mutations in TUBB2B and TUBA1A.

Brain 2013 Feb 29;136(Pt 2):536-48. Epub 2013 Jan 29.

Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, UK.

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. Read More

View Article and Full-Text PDF
February 2013

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations.

Eur J Hum Genet 2012 Sep 15;20(9):995-8. Epub 2012 Feb 15.

Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer - University of Florence, Florence, Italy.

The purpose of the study is to explore the causative role of TUBB2B gene mutations in patients with different malformations of cortical development. We collected and evaluated clinical and MRI data of a cohort of 128 consecutive patients (61 females and 67 males) in whom brain MRI had detected a spectrum of malformations of cortical development including polymicrogyria or pachygyria, who were mutation-negative to other possible causative genes. Mutation analysis of the TUBB2B gene was performed. Read More

View Article and Full-Text PDF
September 2012

A mutation in Tubb2b, a human polymicrogyria gene, leads to lethality and abnormal cortical development in the mouse.

Hum Mol Genet 2013 Oct 31;22(20):4053-63. Epub 2013 May 31.

Present address: Divisions of Human Genetics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Human cortical malformations, including lissencephaly, polymicrogyria and other diseases of neurodevelopment, have been associated with mutations in microtubule subunits and microtubule-associated proteins. Here we report our cloning of the brain dimple (brdp) mouse mutation, which we recovered from an ENU screen for recessive perinatal phenotypes affecting neurodevelopment. We identify the causal mutation in the tubulin, beta-2b (Tubb2b) gene as a missense mutation at a highly conserved residue (N247S). Read More

View Article and Full-Text PDF
October 2013

TUBA1A mutations: from isolated lissencephaly to familial polymicrogyria.

Neurology 2011 Mar;76(11):988-92

Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.

Background: Mutations in the TUBA1A gene have been reported in patients with lissencephaly and perisylvian pachygyria.

Methods: Twenty-five patients with malformations of cortical development ranging from lissencephaly to polymicrogyria were screened for mutations in TUBA1A.

Results: Two novel heterozygous missense mutations in TUBA1A were identified: c. Read More

View Article and Full-Text PDF
March 2011