Journal article
TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins
Human Molecular Genetics, Vol.19(14), pp.2817-2827
2010
Abstract
We previously showed that mutations in LIS1 and DCX account for ~85% of patients with the classic form of lissencephaly (LIS). Some rare forms of LIS are associated with a disproportionately small cerebellum, referred to as lissencephaly with cerebellar hypoplasia (LCH). Tubulin alpha1A (TUBA1A), encoding a critical structural subunit of microtubules, has recently been implicated in LIS. Here, we screen the largest cohort of unexplained LIS patients examined to date to determine: (i) the frequency of TUBA1A mutations in patients with lissencephaly, (ii) the spectrum of phenotypes associated with TUBA1A mutations and (iii) the functional consequences of different TUBA1A mutations on microtubule function. We identified novel and recurrent TUBA1A mutations in ~1% of children with classic LIS and in ~30% of children with LCH, making this the first major gene associated with the rare LCH phenotype. We also unexpectedly found a TUBA1A mutation in one child with agenesis of the corpus callosum and cerebellar hypoplasia without LIS. Thus, our data demonstrate a wider spectrum of phenotypes than previously reported and allow us to propose new recommendations for clinical testing. We also provide cellular and structural data suggesting that LIS-associated mutations of TUBA1A operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins (MAPs). © The Author 2010. Published by Oxford University Press.
Details
- Title
- TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins
- Authors
- Ravinesh A Kumar (Author) - University of Chicago, United StatesD T Pilz (Author) - University Hospital of Wales, United KingdomT D Babatz (Author) - University of Chicago, United StatesT D Cushion (Author) - Swansea University, United KingdomK Harvey (Author) - University College London, United KingdomM Topf (Author) - University of London, United KingdomL Yates (Author) - International Centre for Life, United KingdomS Robb (Author) - Great Ormond Street Hospital, United KingdomG Uyanik (Author) - University Medical Center Hamburg-Eppendorf, GermanyG M Mancini (Author) - Erasmus University Medical Center, NetherlandsM I Rees (Author) - University Hospital of Wales, United KingdomRobert J Harvey (Author) - University College London, United KingdomW B Dobyns (Author) - University of Chicago, United States
- Publication details
- Human Molecular Genetics, Vol.19(14), pp.2817-2827
- Publisher
- Oxford University Press
- Date published
- 2010
- DOI
- 10.1093/hmg/ddq182
- ISSN
- 0964-6906
- Copyright note
- Copyright © The Author 2010. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- Organisation Unit
- School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99450478202621
- Output Type
- Journal article
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