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Human Molecular Genetics Advance Access published online on April 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl089
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© The Author 2006. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received February 14, 2006
Revised March 28, 2006
Accepted March 28, 2006

Article

The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration

Silvia Paracchini 1, Ankur Thomas 2, Sandra Castro 3, Cecilia Lai 4, Murugan Paramasivam 2, Yu Wang 2, Brendan J. Keating 1, Jennifer M. Taylor 1, Douglas F. Hacking 5, Thomas Scerri 1, Clyde Francks 1, Alex J. Richardson 6, Richard Wade-Martins 1, John F. Stein 6, Julian C. Knight 1, Andrew J. Copp 3, Joseph LoTurco 2, and Anthony P. Monaco 1 *

1 Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
2 Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06268-4156
3 Neural Development Unit, Institute of Child Health, University College London, London WC1N 1EH, UK
4 Neural Development Unit, Institute of Child Health, University College London, London WC1N 1EH, UK; Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London WC1E 6BT
5 Division of Molecular Medicine, Walter and Eliza Hall Institute, 1G, Royal Parade, Parkville, VIC, 3050, Australia
6 Department of Physiology, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.

* To whom correspondence should be addressed.
Anthony P. Monaco, E-mail: anthony.monaco{at}well.ox.ac.uk


  Abstract

Dyslexia is one of the most prevalent childhood cognitive disorders, affecting approximately five percent of school-age children. We have recently identified a risk haplotype associated with dyslexia on chromosome 6p22.2 which spans the TTRAP gene and portions of THEM2 and KIAA0319. Here we show that in the presence of the risk haplotype, the expression of the KIAA0319 gene is reduced but the expression of the other two genes remains unaffected. Using in situ hybridization we detect a very distinct expression pattern of the KIAA0319 gene in the developing cerebral neocortex of mouse and human fetuses. Moreover, interference with rat Kiaa0319 expression in utero leads to impaired neuronal migration in the developing cerebral neocortex. These data suggest a direct link between a specific genetic background and a biological mechanism leading to the development of dyslexia: the risk haplotype on chromosome 6p22.2 down-regulates the KIAA0319 gene which is required for neuronal migration during the formation of the cerebral neocortex.


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