Developmental dyslexia is a common specific childhood learning disorder with a strong heritable component. Previous studies using different genetic approaches have identified several genetic loci and candidate genes for dyslexia. In this article, we have integrated the current knowledge on 14 dyslexia candidate genes suggested by cytogenetic findings, linkage and association studies. We found that 10 of the 14 dyslexia candidate genes (ROBO1, KIAA0319, KIAA0319L, S100B, DOCK4, FMR1, DIP2A, GTF2I, DYX1C1 and DCDC2) fit into a theoretical molecular network involved in neuronal migration and neurite outgrowth. Based on this, we also propose three novel dyslexia candidate genes (SLIT2, HMGB1 and VAPA) from known linkage regions, and we discuss the possible involvement of genes emerging from the two reported genome-wide association studies for reading impairment-related phenotypes in the identified network.
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Grigorenko EL, Wood FB, Meyer MS, Hart LA, Speed WC, Shuster A et al. Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15. Am J Hum Genet 1997; 60: 27–39.
Fisher SE, Francks C, Marlow AJ, MacPhie IL, Newbury DF, Cardon LR et al. Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nat Genet 2002; 30: 86–91.
Francks C, Paracchini S, Smith SD, Richardson AJ, Scerri TS, Cardon LR et al. A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States. Am J Hum Genet 2004; 75: 1046–1058.
de Kovel CG, Hol FA, Heister JG, Willemen JJ, Sandkuijl LA, Franke B et al. Genomewide scan identifies susceptibility locus for dyslexia on Xq27 in an extended Dutch family. J Med Genet 2004; 41: 652–657.
Petryshen TL, Pauls DL . The genetics of reading disability. Curr Psychiatry Rep 2009; 11: 149–155.
Fletcher JM . Dyslexia: the evolution of a scientific concept. J Int Neuropsychol Soc 2009; 15: 501–508.
Flannery KA, Liederman J, Daly L, Schultz J . Male prevalence for reading disability is found in a large sample of black and white children free from ascertainment bias. J Int Neuropsychol Soc 2000; 6: 433–442.
Scerri TS, Schulte-Korne G . Genetics of developmental dyslexia. Eur Child Adolesc Psychiatry 2010; 19: 179–197.
Shaywitz SE, Shaywitz BA . Paying attention to reading: the neurobiology of reading and dyslexia. Dev Psychopathol 2008; 20: 1329–1349.
Hoskyn M . Neurobiological and experiential origins of dyslexia: an introduction. Dev Neuropsychol 2008; 33: 659–662.
Galaburda AM, LoTurco J, Ramus F, Fitch RH, Rosen GD . From genes to behavior in developmental dyslexia. Nat Neurosci 2006; 9: 1213–1217.
Schaefer AW, Schoonderwoert VT, Ji L, Mederios N, Danuser G, Forscher P . Coordination of actin filament and microtubule dynamics during neurite outgrowth. Dev Cell 2008; 15: 146–162.
Gabel LA, Gibson CJ, Gruen JR, Loturco JJ . Progress towards a cellular neurobiology of reading disability. Neurobiol Dis 2010; 38: 173–180.
Rabin M, Wen XL, Hepburn M, Lubs HA, Feldman E, Duara R . Suggestive linkage of developmental dyslexia to chromosome 1p34-p36. Lancet 1993; 342: 178.
Grigorenko EL, Wood FB, Meyer MS, Pauls JE, Hart LA, Pauls DL . Linkage studies suggest a possible locus for developmental dyslexia on chromosome 1p. Am J Med Genet 2001; 105: 120–129.
Tzenova J, Kaplan BJ, Petryshen TL, Field LL . Confirmation of a dyslexia susceptibility locus on chromosome 1p34-p36 in a set of 100 Canadian families. Am J Med Genet B Neuropsychiatr Genet 2004; 127B: 117–124.
de Kovel CG, Franke B, Hol FA, Lebrec JJ, Maassen B, Brunner H et al. Confirmation of dyslexia susceptibility loci on chromosomes 1p and 2p, but not 6p in a Dutch sib-pair collection. Am J Med Genet B Neuropsychiatr Genet 2008; 147: 294–300.
Platko JV, Wood FB, Pelser I, Meyer M, Gericke GS, O’Rourke J et al. Association of reading disability on chromosome 6p22 in the Afrikaner population. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 1278–1287.
Fagerheim T, Raeymaekers P, Tonnessen FE, Pedersen M, Tranebjaerg L, Lubs HA . A new gene (DYX3) for dyslexia is located on chromosome 2. J Med Genet 1999; 36: 664–669.
Petryshen TL, Kaplan BJ, Hughes ML, Tzenova J, Field LL . Supportive evidence for the DYX3 dyslexia susceptibility gene in Canadian families. J Med Genet 2002; 39: 125–126.
Francks C, Fisher SE, Olson RK, Pennington BF, Smith SD, DeFries JC et al. Fine mapping of the chromosome 2p12–16 dyslexia susceptibility locus: quantitative association analysis and positional candidate genes SEMA4F and OTX1. Psychiatr Genet 2002; 12: 35–41.
Kaminen N, Hannula-Jouppi K, Kestila M, Lahermo P, Muller K, Kaaranen M et al. A genome scan for developmental dyslexia confirms linkage to chromosome 2p11 and suggests a new locus on 7q32. J Med Genet 2003; 40: 340–345.
Peyrard-Janvid M, Anthoni H, Onkamo P, Lahermo P, Zucchelli M, Kaminen N et al. Fine mapping of the 2p11 dyslexia locus and exclusion of TACR1 as a candidate gene. Hum Genet 2004; 114: 510–516.
Anthoni H, Zucchelli M, Matsson H, Muller-Myhsok B, Fransson I, Schumacher J et al. A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia. Hum Mol Genet 2007; 16: 667–677.
Raskind WH, Igo RP, Chapman NH, Berninger VW, Thomson JB, Matsushita M et al. A genome scan in multigenerational families with dyslexia: identification of a novel locus on chromosome 2q that contributes to phonological decoding efficiency. Mol Psychiatry 2005; 10: 699–711.
Igo Jr RP, Chapman NH, Berninger VW, Matsushita M, Brkanac Z, Rothstein JH et al. Genomewide scan for real-word reading subphenotypes of dyslexia: novel chromosome 13 locus and genetic complexity. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 15–27.
Nopola-Hemmi J, Myllyluoma B, Haltia T, Taipale M, Ollikainen V, Ahonen T et al. A dominant gene for developmental dyslexia on chromosome 3. J Med Genet 2001; 38: 658–664.
Cardon LR, Smith SD, Fulker DW, Kimberling WJ, Pennington BF, DeFries JC . Quantitative trait locus for reading disability on chromosome 6. Science 1994; 266: 276–279.
Kaplan DE, Gayan J, Ahn J, Won TW, Pauls D, Olson RK et al. Evidence for linkage and association with reading disability on 6p21.3–22. Am J Hum Genet 2002; 70: 1287–1298.
Deffenbacher KE, Kenyon JB, Hoover DM, Olson RK, Pennington BF, DeFries JC et al. Refinement of the 6p21.3 quantitative trait locus influencing dyslexia: linkage and association analyses. Hum Genet 2004; 115: 128–138.
Bates TC, Luciano M, Castles A, Coltheart M, Wright MJ, Martin NG . Replication of reported linkages for dyslexia and spelling and suggestive evidence for novel regions on chromosomes 4 and 17. Eur J Hum Genet 2007; 15: 194–203.
Petryshen TL, Kaplan BJ, Fu LM, de French NS, Tobias R, Hughes ML et al. Evidence for a susceptibility locus on chromosome 6q influencing phonological coding dyslexia. Am J Med Genet 2001; 105: 507–517.
Smith SD, Kimberling WJ, Pennington BF, Lubs HA . Specific reading disability: identification of an inherited form through linkage analysis. Science 1983; 219: 1345–1347.
Schulte-Korne G, Grimm T, Nothen MM, Muller-Myhsok B, Cichon S, Vogt IR et al. Evidence for linkage of spelling disability to chromosome 15. Am J Hum Genet 1998; 63: 279–282.
Morris DW, Robinson L, Turic D, Duke M, Webb V, Milham C et al. Family-based association mapping provides evidence for a gene for reading disability on chromosome 15q. Hum Mol Genet 2000; 9: 843–848.
Chapman NH, Igo RP, Thomson JB, Matsushita M, Brkanac Z, Holzman T et al. Linkage analyses of four regions previously implicated in dyslexia: confirmation of a locus on chromosome 15q. Am J Med Genet B Neuropsychiatr Genet 2004; 131B: 67–75.
Schumacher J, Konig IR, Schroder T, Duell M, Plume E, Propping P et al. Further evidence for a susceptibility locus contributing to reading disability on chromosome 15q15-q21. Psychiatr Genet 2008; 18: 137–142.
Seshadri S, DeStefano AL, Au R, Massaro JM, Beiser AS, Kelly-Hayes M et al. Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham Study. BMC Med Genet 2007; 8 (Suppl 1): S15.
Hsiung GY, Kaplan BJ, Petryshen TL, Lu S, Field LL . A dyslexia susceptibility locus (DYX7) linked to dopamine D4 receptor (DRD4) region on chromosome 11p15.5. Am J Med Genet B Neuropsychiatr Genet 2004; 125B: 112–119.
Schumacher J, Hoffmann P, Schmal C, Schulte-Korne G, Nothen MM . Genetics of dyslexia: the evolving landscape. J Med Genet 2007; 44: 289–297.
Meaburn EL, Harlaar N, Craig IW, Schalkwyk LC, Plomin R . Quantitative trait locus association scan of early reading disability and ability using pooled DNA and 100K SNP microarrays in a sample of 5760 children. Mol Psychiatry 2008; 13: 729–740.
Roeske D, Ludwig KU, Neuhoff N, Becker J, Bartling J, Bruder J et al. First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children. Mol Psychiatry; 29 September 2009 (e-pub ahead of print).
Taipale M, Kaminen N, Nopola-Hemmi J, Haltia T, Myllyluoma B, Lyytinen H et al. A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proc Natl Acad Sci USA 2003; 100: 11553–11558.
Tapia-Paez I, Tammimies K, Massinen S, Roy AL, Kere J . The complex of TFII-I, PARP1, and SFPQ proteins regulates the DYX1C1 gene implicated in neuronal migration and dyslexia. FASEB J 2008; 22: 3001–3009.
Nopola-Hemmi J, Taipale M, Haltia T, Lehesjoki AE, Voutilainen A, Kere J . Two translocations of chromosome 15q associated with dyslexia. J Med Genet 2000; 37: 771–775.
Cope NA, Hill G, van den BM, Harold D, Moskvina V, Green EK et al. No support for association between dyslexia susceptibility 1 candidate 1 and developmental dyslexia. Mol Psychiatry 2005; 10: 237–238.
Marino C, Giorda R, Luisa LM, Vanzin L, Salandi N, Nobile M et al. A family-based association study does not support DYX1C1 on 15q21.3 as a candidate gene in developmental dyslexia. Eur J Hum Genet 2005; 13: 491–499.
Meng H, Hager K, Held M, Page GP, Olson RK, Pennington BF et al. TDT-association analysis of EKN1 and dyslexia in a Colorado twin cohort. Hum Genet 2005; 118: 87–90.
Bellini G, Bravaccio C, Calamoneri F, Donatella CM, Fiorillo P, Gagliano A et al. No evidence for association between dyslexia and DYX1C1 functional variants in a group of children and adolescents from Southern Italy. J Mol Neurosci 2005; 27: 311–314.
Scerri TS, Fisher SE, Francks C, MacPhie IL, Paracchini S, Richardson AJ et al. Putative functional alleles of DYX1C1 are not associated with dyslexia susceptibility in a large sample of sibling pairs from the UK. J Med Genet 2004; 41: 853–857.
Wigg KG, Couto JM, Feng Y, Anderson B, Cate-Carter TD, Macciardi F et al. Support for EKN1 as the susceptibility locus for dyslexia on 15q21. Mol Psychiatry 2004; 9: 1111–1121.
Brkanac Z, Chapman NH, Matsushita MM, Chun L, Nielsen K, Cochrane E et al. Evaluation of candidate genes for DYX1 and DYX2 in families with dyslexia. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 556–560.
Marino C, Citterio A, Giorda R, Facoetti A, Menozzi G, Vanzin L et al. Association of short-term memory with a variant within DYX1C1 in developmental dyslexia. Genes Brain Behav 2007; 6: 640–646.
Dahdouh F, Anthoni H, Tapia-Paez I, Peyrard-Janvid M, Schulte-Korne G, Warnke A et al. Further evidence for DYX1C1 as a susceptibility factor for dyslexia. Psychiatr Genet 2009; 19: 59–63.
Bates TC, Lind PA, Luciano M, Montgomery GW, Martin NG, Wright MJ . Dyslexia and DYX1C1: deficits in reading and spelling associated with a missense mutation. Mol Psychiatry; 10 November 2009 (e-pub ahead of print).
Poelmans G, Engelen JJ, Van Lent-Albrechts J, Smeets HJ, Schoenmakers E, Franke B et al. Identification of novel dyslexia candidate genes through the analysis of a chromosomal deletion. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 140–147.
Wang Y, Paramasivam M, Thomas A, Bai J, Kaminen-Ahola N, Kere J et al. DYX1C1 functions in neuronal migration in developing neocortex. Neuroscience 2006; 143: 515–522.
Rosen GD, Bai J, Wang Y, Fiondella CG, Threlkeld SW, Loturco JJ et al. Disruption of neuronal migration by RNAi of Dyx1c1 results in neocortical and hippocampal malformations. Cereb Cortex 2007; 17: 2562–2572.
Threlkeld SW, McClure MM, Bai J, Wang Y, Loturco JJ, Rosen GD et al. Developmental disruptions and behavioral impairments in rats following in utero RNAi of Dyx1c1. Brain Res Bull 2007; 71: 508–514.
Kim YJ, Huh JW, Kim DS, Bae MI, Lee JR, Ha HS et al. Molecular characterization of the DYX1C1 gene and its application as a cancer biomarker. J Cancer Res Clin Oncol 2009; 135: 265–270.
Chen Y, Zhao M, Wang S, Chen J, Wang Y, Cao Q et al. A novel role for DYX1C1, a chaperone protein for both Hsp70 and Hsp90, in breast cancer. J Cancer Res Clin Oncol 2009; 135: 1265–1276.
Massinen S, Tammimies K, Tapia-Paez I, Matsson H, Hokkanen ME, Soderberg O et al. Functional interaction of DYX1C1 with estrogen receptors suggests involvement of hormonal pathways in dyslexia. Hum Mol Genet 2009; 18: 2802–2812.
Swanson HL, Howard CB, Saez L . Do different components of working memory underlie different subgroups of reading disabilities? J Learn Disabil 2006; 39: 252–269.
Londin ER, Meng H, Gruen JR . A transcription map of the 6p22.3 reading disability locus identifying candidate genes. BMC Genomics 2003; 4: 25.
Meng H, Smith SD, Hager K, Held M, Liu J, Olson RK et al. DCDC2 is associated with reading disability and modulates neuronal development in the brain. Proc Natl Acad Sci USA 2005; 102: 17053–17058.
Ludwig KU, Schumacher J, Schulte-Korne G, Konig IR, Warnke A, Plume E et al. Investigation of the DCDC2 intron 2 deletion/compound short tandem repeat polymorphism in a large German dyslexia sample. Psychiatr Genet 2008; 18: 310–312.
Schumacher J, Anthoni H, Dahdouh F, Konig IR, Hillmer AM, Kluck N et al. Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia. Am J Hum Genet 2006; 78: 52–62.
Meda SA, Gelernter J, Gruen JR, Calhoun VD, Meng H, Cope NA et al. Polymorphism of DCDC2 reveals differences in cortical morphology of healthy individuals-a preliminary voxel based morphometry study. Brain Imaging Behav 2008; 2: 21–26.
Wilcke A, Weissfuss J, Kirsten H, Wolfram G, Boltze J, Ahnert P . The role of gene DCDC2 in German dyslexics. Ann Dyslexia 2009; 59: 1–11.
Lind PA, Luciano M, Wright MJ, Montgomery GW, Martin NG, Bates TC . Dyslexia and DCDC2: normal variation in reading and spelling is associated with DCDC2 polymorphisms in an Australian population sample. Eur J Hum Genet 2010; 18: 668–673.
Cope N, Harold D, Hill G, Moskvina V, Stevenson J, Holmans P et al. Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia. Am J Hum Genet 2005; 76: 581–591.
Harold D, Paracchini S, Scerri T, Dennis M, Cope N, Hill G et al. Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia. Mol Psychiatry 2006; 11: 1085–1091, 1061.
Luciano M, Lind PA, Duffy DL, Castles A, Wright MJ, Montgomery GW et al. A haplotype spanning KIAA0319 and TTRAP is associated with normal variation in reading and spelling ability. Biol Psychiatry 2007; 62: 811–817.
Paracchini S, Steer CD, Buckingham LL, Morris AP, Ring S, Scerri T et al. Association of the KIAA0319 dyslexia susceptibility gene with reading skills in the general population. Am J Psychiatry 2008; 165: 1576–1584.
Paracchini S, Thomas A, Castro S, Lai C, Paramasivam M, Wang Y et al. The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration. Hum Mol Genet 2006; 15: 1659–1666.
Dennis MY, Paracchini S, Scerri TS, Prokunina-Olsson L, Knight JC, Wade-Martins R et al. A common variant associated with dyslexia reduces expression of the KIAA0319 gene. PLoS Genet 2009; 5: e1000436.
Ludwig KU, Roeske D, Schumacher J, Schulte-Korne G, Konig IR, Warnke A et al. Investigation of interaction between DCDC2 and KIAA0319 in a large German dyslexia sample. J Neural Transm 2008; 115: 1587–1589.
Coquelle FM, Levy T, Bergmann S, Wolf SG, Bar-El D, Sapir T et al. Common and divergent roles for members of the mouse DCX superfamily. Cell Cycle 2006; 5: 976–983.
Reiner O, Coquelle FM, Peter B, Levy T, Kaplan A, Sapir T et al. The evolving doublecortin (DCX) superfamily. BMC Genomics 2006; 7: 188.
Gleeson JG, Lin PT, Flanagan LA, Walsh CA . Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 1999; 23: 257–271.
Burbridge TJ, Wang Y, Volz AJ, Peschansky VJ, Lisann L, Galaburda AM et al. Postnatal analysis of the effect of embryonic knockdown and overexpression of candidate dyslexia susceptibility gene homolog Dcdc2 in the rat. Neuroscience 2008; 152: 723–733.
Velayos-Baeza A, Toma C, Paracchini S, Monaco AP . The dyslexia-associated gene KIAA0319 encodes highly N- and O-glycosylated plasma membrane and secreted isoforms. Hum Mol Genet 2008; 17: 859–871.
Peschansky VJ, Burbridge TJ, Volz AJ, Fiondella C, Wissner-Gross Z, Galaburda AM et al. The effect of variation in expression of the candidate dyslexia susceptibility gene homolog Kiaa0319 on neuronal migration and dendritic morphology in the rat. Cereb Cortex 2010; 20: 884–897.
Velayos-Baeza A, Toma C, da RS, Paracchini S, Monaco AP . Alternative splicing in the dyslexia-associated gene KIAA0319. Mamm Genome 2007; 18: 627–634.
Hannula-Jouppi K, Kaminen-Ahola N, Taipale M, Eklund R, Nopola-Hemmi J, Kaariainen H et al. The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia. PLoS Genet 2005; 1: e50.
Stein E, Tessier-Lavigne M . Hierarchical organization of guidance receptors: silencing of netrin attraction by slit through a Robo/DCC receptor complex. Science 2001; 291: 1928–1938.
Couto JM, Gomez L, Wigg K, Cate-Carter T, Archibald J, Anderson B et al. The KIAA0319-like (KIAA0319L) gene on chromosome 1p34 as a candidate for reading disabilities. J Neurogenet 2008; 22: 295–313.
Aruga J, Yokota N, Mikoshiba K . Human SLITRK family genes: genomic organization and expression profiling in normal brain and brain tumor tissue. Gene 2003; 315: 87–94.
Bailey DB, Raspa M, Holiday D, Bishop E, Olmsted M . Functional skills of individuals with fragile x syndrome: a lifespan cross-sectional analysis. Am J Intellect Dev Disabil 2009; 114: 289–303.
Wolff PH, Gardner J, Lappen J, Paccia J, Meryash D . Variable expression of the fragile X syndrome in heterozygous females of normal intelligence. Am J Med Genet 1988; 30: 213–225.
Cornish KM, Kogan CS, Li L, Turk J, Jacquemont S, Hagerman RJ . Lifespan changes in working memory in fragile X premutation males. Brain Cogn 2009; 69: 551–558.
Shang Y, Wang H, Mercaldo V, Li X, Chen T, Zhuo M . Fragile X mental retardation protein is required for chemically-induced long-term potentiation of the hippocampus in adult mice. J Neurochem 2009; 111: 635–646.
Veneri M, Zalfa F, Bagni C . FMRP and its target RNAs: fishing for the specificity. Neuroreport 2004; 15: 2447–2450.
Zalfa F, Achsel T, Bagni C . mRNPs, polysomes or granules: FMRP in neuronal protein synthesis. Curr Opin Neurobiol 2006; 16: 265–269.
UniProt Consortium. The universal protein resource (UniProt) in 2010. Nucleic Acids Res 2010; 38: D142–D148.
Lee A, Li W, Xu K, Bogert BA, Su K, Gao FB . Control of dendritic development by the Drosophila fragile X-related gene involves the small GTPase Rac1. Development 2003; 130: 5543–5552.
Bolduc FV, Bell K, Rosenfelt C, Cox H, Tully T . Fragile x mental retardation 1 and filamin a interact genetically in Drosophila long-term memory. Front Neural Circuits 2010; 3: 22.
Robertson SP, Twigg SR, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 2003; 33: 487–491.
Lu J, Sheen V . Periventricular heterotopia. Epilepsy Behav 2005; 7: 143–149.
McCann MV, Pongonis SJ, Golomb MR, Edwards-Brown M, Christensen CK, Sokol DK . Like father, like son: periventricular nodular heterotopia and nonverbal learning disorder. J Child Neurol 2008; 23: 950–953.
Yu G, Zerucha T, Ekker M, Rubenstein JL . Evidence that GRIP, a PDZ-domain protein which is expressed in the embryonic forebrain, co-activates transcription with DLX homeodomain proteins. Brain Res Dev Brain Res 2001; 130: 217–230.
Ouchi N, Asaumi Y, Ohashi K, Higuchi A, Sono-Romanelli S, Oshima Y et al. Disco-interacting protein 2 homolog A functions as a follistatin-like 1 receptor. J Biol Chem 2010; 285: 7127–7134.
Rountree MR, Bachman KE, Baylin SB . DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 2000; 25: 269–277.
Bai S, Ghoshal K, Jacob ST . Identification of T-cadherin as a novel target of DNA methyltransferase 3B and its role in the suppression of nerve growth factor-mediated neurite outgrowth in PC12 cells. J Biol Chem 2006; 281: 13604–13611.
Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 2009; 459: 55–60.
Rothermundt M, Peters M, Prehn JH, Arolt V . S100B in brain damage and neurodegeneration. Microsc Res Tech 2003; 60: 614–632.
Huttunen HJ, Kuja-Panula J, Sorci G, Agneletti AL, Donato R, Rauvala H . Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem 2000; 275: 40096–40105.
Nishiyama H, Knopfel T, Endo S, Itohara S . Glial protein S100B modulates long-term neuronal synaptic plasticity. Proc Natl Acad Sci USA 2002; 99: 4037–4042.
Pagnamenta AT, Bacchelli E, de Jonge MV, Mirza G, Scerri TS, Minopoli F et al. Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia. Biol Psychiatry 2010; 68: 320–328.
Ueda S, Fujimoto S, Hiramoto K, Negishi M, Katoh H . Dock4 regulates dendritic development in hippocampal neurons. J Neurosci Res 2008; 86: 3052–3061.
Hiramoto K, Negishi M, Katoh H . Dock4 is regulated by RhoG and promotes Rac-dependent cell migration. Exp Cell Res 2006; 312: 4205–4216.
Laing E, Hulme C, Grant J, Karmiloff-Smith A . Learning to read in Williams syndrome: looking beneath the surface of atypical reading development. J Child Psychol Psychiatry 2001; 42: 729–739.
Levy Y, Smith J, Tager-Flusberg H . Word reading and reading-related skills in adolescents with Williams syndrome. J Child Psychol Psychiatry 2003; 44: 576–587.
Temple CM . Developmental and acquired dyslexias. Cortex 2006; 42: 898–910.
Meyer-Lindenberg A, Mervis CB, Berman KF . Neural mechanisms in Williams syndrome: a unique window to genetic influences on cognition and behaviour. Nat Rev Neurosci 2006; 7: 380–393.
Antonell A, Del CM, Magano LF, Kaufmann L, De la IJM, Gallastegui F et al. Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile. J Med Genet 2010; 47: 312–320.
Attree EA, Turner MJ, Cowell N . A virtual reality test identifies the visuospatial strengths of adolescents with dyslexia. Cyberpsychol Behav 2009; 12: 163–168.
Van der Aa N, Rooms L, Vandeweyer G, van den EJ, Reyniers E, Fichera M et al. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. Eur J Med Genet 2009; 52: 94–100.
Hoogenraad CC, Koekkoek B, Akhmanova A, Krugers H, Dortland B, Miedema M et al. Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice. Nat Genet 2002; 32: 116–127.
Beissbarth T, Speed TP . GOstat: find statistically overrepresented Gene Ontologies within a group of genes. Bioinformatics 2004; 20: 1464–1465.
Weir ML, Klip A, Trimble WS . Identification of a human homologue of the vesicle-associated membrane protein (VAMP)-associated protein of 33 kDa (VAP-33): a broadly expressed protein that binds to VAMP. Biochem J 1998; 333 (Part 2): 247–251.
Lotz GP, Brychzy A, Heinz S, Obermann WM . A novel HSP90 chaperone complex regulates intracellular vesicle transport. J Cell Sci 2008; 121: 717–723.
Saita S, Shirane M, Natume T, Iemura S, Nakayama KI . Promotion of neurite extension by protrudin requires its interaction with vesicle-associated membrane protein-associated protein. J Biol Chem 2009; 284: 13766–13777.
Halim ND, Weickert CS, McClintock BW, Hyde TM, Weinberger DR, Kleinman JE et al. Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development. Mol Psychiatry 2003; 8: 797–810.
Lohoff FW, Weller AE, Bloch PJ, Nall AH, Ferraro TN, Berrettini WH . Association between polymorphisms in the vesicle-associated membrane protein-associated protein A (VAPA) gene on chromosome 18p and bipolar disorder. J Neural Transm 2008; 115: 1339–1345.
Di Meglio T, Nguyen-Ba-Charvet KT, Tessier-Lavigne M, Sotelo C, Chedotal A . Molecular mechanisms controlling midline crossing by precerebellar neurons. J Neurosci 2008; 28: 6285–6294.
Chou DK, Zhang J, Smith FI, McCaffery P, Jungalwala FB . Developmental expression of receptor for advanced glycation end products (RAGE), amphoterin and sulfoglucuronyl (HNK-1) carbohydrate in mouse cerebellum and their role in neurite outgrowth and cell migration. J Neurochem 2004; 90: 1389–1401.
Shiota M, Izumi H, Miyamoto N, Onitsuka T, Kashiwagi E, Kidani A et al. Ets regulates peroxiredoxin1 and 5 expressions through their interaction with the high-mobility group protein B1. Cancer Sci 2008; 99: 1950–1959.
Katoh Y, Katoh M . Comparative genomics on SLIT1, SLIT2, and SLIT3 orthologs. Oncol Rep 2005; 14: 1351–1355.
Das D, Peterson RC, Scovell WM . High mobility group B proteins facilitate strong estrogen receptor binding to classical and half-site estrogen response elements and relax binding selectivity. Mol Endocrinol 2004; 18: 2616–2632.
Shekarabi M, Moore SW, Tritsch NX, Morris SJ, Bouchard JF, Kennedy TE . Deleted in colorectal cancer binding netrin-1 mediates cell substrate adhesion and recruits Cdc42, Rac1, Pak1, and N-WASP into an intracellular signaling complex that promotes growth cone expansion. J Neurosci 2005; 25: 3132–3141.
Frost JA, Steen H, Shapiro P, Lewis T, Ahn N, Shaw PE et al. Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. EMBO J 1997; 16: 6426–6438.
Ghose A, Van VD . GAPs in Slit-Robo signaling. Bioessays 2002; 24: 401–404.
Wong K, Ren XR, Huang YZ, Xie Y, Liu G, Saito H et al. Signal transduction in neuronal migration: roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathway. Cell 2001; 107: 209–221.
Wang L, Li S, Jungalwala FB . Receptor for advanced glycation end products (RAGE) mediates neuronal differentiation and neurite outgrowth. J Neurosci Res 2008; 86: 1254–1266.
Bianchi R, Giambanco I, Donato R . S100B/RAGE-dependent activation of microglia via NF-kappaB and AP-1 co-regulation of COX-2 expression by S100B, IL-1beta and TNF-alpha. Neurobiol Aging 2010; 31: 665–677.
Bassi R, Giussani P, Anelli V, Colleoni T, Pedrazzi M, Patrone M et al. HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration. J Neurooncol 2008; 87: 23–33.
Dhawan P, Richmond A . A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells. J Biol Chem 2002; 277: 7920–7928.
Stamatovic SM, Keep RF, Mostarica-Stojkovic M, Andjelkovic AV . CCL2 regulates angiogenesis via activation of Ets-1 transcription factor. J Immunol 2006; 177: 2651–2661.
Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S . The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J Neurosci 2000; 20: 4563–4572.
Kim DW, Cochran BH . JAK2 activates TFII-I and regulates its interaction with extracellular signal-regulated kinase. Mol Cell Biol 2001; 21: 3387–3397.
Paradisi A, Maisse C, Bernet A, Coissieux MM, Maccarrone M, Scoazec JY et al. NF-kappaB regulates netrin-1 expression and affects the conditional tumor suppressive activity of the netrin-1 receptors. Gastroenterology 2008; 135: 1248–1257.
Ammirante M, Rosati A, Gentilella A, Festa M, Petrella A, Marzullo L et al. The activity of hsp90 alpha promoter is regulated by NF-kappa B transcription factors. Oncogene 2008; 27: 1175–1178.
Fujioka S, Niu J, Schmidt C, Sclabas GM, Peng B, Uwagawa T et al. NF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity. Mol Cell Biol 2004; 24: 7806–7819.
Itoh Y, Hayashi H, Miyazawa K, Kojima S, Akahoshi T, Onozaki K . 17beta-estradiol induces IL-1alpha gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor alpha (ERalpha) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 from ERalpha. J Immunol 2007; 178: 3059–3066.
Singh M, Setalo Jr G, Guan X, Warren M, Toran-Allerand CD . Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. J Neurosci 1999; 19: 1179–1188.
Shirazi FS, Kele J, Vilar M, Paratcha G, Ledda F . Tiam1 as a signaling mediator of nerve growth factor-dependent neurite outgrowth. PLoS One 2010; 5: e9647.
Yoo AS, Staahl BT, Chen L, Crabtree GR . MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 2009; 460: 642–646.
Hintsch G, Zurlinden A, Meskenaite V, Steuble M, Fink-Widmer K, Kinter J et al. The calsyntenins--a family of postsynaptic membrane proteins with distinct neuronal expression patterns. Mol Cell Neurosci 2002; 21: 393–409.
Papassotiropoulos A, Stephan DA, Huentelman MJ, Hoerndli FJ, Craig DW, Pearson JV et al. Common Kibra alleles are associated with human memory performance. Science 2006; 314: 475–478.
Araki Y, Kawano T, Taru H, Saito Y, Wada S, Miyamoto K et al. The novel cargo Alcadein induces vesicle association of kinesin-1 motor components and activates axonal transport. EMBO J 2007; 26: 1475–1486.
Kawauchi K, Araki K, Tobiume K, Tanaka N . p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol 2008; 10: 611–618.
Alonso A, Moreno M, Ordonez P, Fernandez R, Perez C, Diaz F et al. Chronic estradiol treatment improves brain homeostasis during aging in female rats. Endocrinology 2008; 149: 57–72.
Weisova P, Concannon CG, Devocelle M, Prehn JH, Ward MW . Regulation of glucose transporter 3 surface expression by the AMP-activated protein kinase mediates tolerance to glutamate excitation in neurons. J Neurosci 2009; 29: 2997–3008.
We gratefully acknowledge the families who have made all these studies possible. We are also indebted to the many investigators whose work drives the dyslexia genetics field forward. This work was supported by a research grant from the ‘Hersenstichting Nederland’ (Brain Foundation of The Netherlands).
The authors declare no conflict of interest.
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Poelmans, G., Buitelaar, J., Pauls, D. et al. A theoretical molecular network for dyslexia: integrating available genetic findings. Mol Psychiatry 16, 365–382 (2011). https://doi.org/10.1038/mp.2010.105
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