DCDC2 Is Associated with Reading Disability and Modulates Neuronal Development in the Brain

DYX2 on 6p22 is the most replicated reading disability (RD) locus. By saturating a previously identified peak of association with single nucleotide polymorphism markers, we identified a large polymorphic deletion that encodes tandem repeats of putative brain-related transcription factor binding site...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 47; pp. 17053 - 17058
Main Authors Haiying Meng, Smith, Shelley D., Karl Hager, Held, Matthew, Jonathan Liu, Olson, Richard K., Pennington, Bruce F., DeFries, John C., Gelernter, Joel, Thomas O'Reilly-Pol, Somlo, Stefan, Skudlarski, Pawel, Shaywitz, Sally E., Shaywitz, Bennett A., Karen Marchione, Wang, Yu, Murugan Paramasivam, LoTurco, Joseph J., Page, Grier P., Jeffrey R. Gruen
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 22.11.2005
National Acad Sciences
SeriesFrom the Cover
Subjects
Adult
Aged
Alleles
Biological Sciences
Brain
Brain - cytology
Brain - physiology
Cell Differentiation - genetics
Cell Migration Inhibition
Cell Movement - genetics
Dyslexia
Dyslexia - genetics
Dyslexia - pathology
Female
Genetic Predisposition to Disease
Genomics
Haplotypes
Humans
Introns
Linkage Disequilibrium
Male
Market disequilibrium
Middle Aged
Neurons
Neurons - cytology
Neurons - physiology
Phenotypes
Reverse Transcriptase Polymerase Chain Reaction
RNA Interference
Sequence Deletion
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Summary:DYX2 on 6p22 is the most replicated reading disability (RD) locus. By saturating a previously identified peak of association with single nucleotide polymorphism markers, we identified a large polymorphic deletion that encodes tandem repeats of putative brain-related transcription factor binding sites in intron 2 of DCDC2. Alleles of this compound repeat are in significant disequilibrium with multiple reading traits. RT-PCR data show that DCDC2 localizes to the regions of the brain where fluent reading occurs, and RNA interference studies show that down-regulation alters neuronal migration. The statistical and functional studies are complementary and are consistent with the latest clinical imaging data for RD. Thus, we propose that DCDC2 is a candidate gene for RD.
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Data deposition: The sequences reported in this paper have been deposited in the dbSTS database, www.ncbi.nlm.nih.gov/projects/SNP (dbSTS ID no. 808238).
Conflict of interest statement: No conflicts declared.
To whom correspondence should be addressed. E-mail: jeffrey.gruen@yale.edu.
Author contributions: H.M., J.J.L., and J.R.G. designed research; H.M., K.H., M.H., T.O.-P., Y.W., and M.P. performed research; S.D.S., J.L., R.K.O., B.F.P., J.C.D., J.G., S.S., P.S., S.E.S., B.A.S., K.M., and J.J.L. contributed new reagents/analytic tools; H.M., J.L., G.P.P., and J.R.G. analyzed data; and H.M., J.J.L., and J.R.G. wrote the paper.
Abbreviations: CLDRC, Colorado Learning Disabilities Research Center; DISC, discriminant score; ID, identification; IQ, intelligence quotient; LOH, loss-of-heterozygosity; RD, reading disability; RNAi, RNA interference; shRNA, small hairpin RNA; SNP, single nucleotide polymorphism; STR, short tandem repeat.
Communicated by Sherman M. Weissman, Yale University School of Medicine, New Haven, CT, October 3, 2005
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0508591102