Progress towards a cellular neurobiology of reading disability

Neurobiology of Disease 38 (2010) 173–180

Contents lists available at ScienceDirect

Neurobiology of Disease j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y n b d i

Review

Progress towards a cellular neurobiology of reading disability Lisa A. Gabel a,1, Christopher J. Gibson b,1, Jeffrey R. Gruen b,c,d, Joseph J. LoTurco e,⁎ a

Department of Psychology and Program in Neuroscience, Lafayette College, Easton, PA, USA Department of Pediatrics, Yale Child Health Research Center, Yale University School of Medicine, New Haven, CT, USA c Department of Genetics, Yale University School of Medicine, New Haven, CT, USA d Department of Investigational Medicine Program, Yale University School of Medicine, New Haven, CT, USA e Department of Physiology and Neurobiology, University of Connecticut, Storrs 06268-3156, CT, USA b

a r t i c l e

i n f o

Article history: Received 23 May 2009 Revised 25 June 2009 Accepted 28 June 2009 Available online 17 July 2009 Keywords: Dyslexia Neocortex Neuronal migration Development DCDC2 KIAA0319 DYX1C1

a b s t r a c t Reading Disability (RD) is a significant impairment in reading accuracy, speed and/or comprehension despite adequate intelligence and educational opportunity. RD affects 5–12% of readers, has a well-established genetic risk, and is of unknown neurobiological cause or causes. In this review we discuss recent findings that revealed neuroanatomic anomalies in RD, studies that identified 3 candidate genes (KIAA0319, DYX1C1, and DCDC2), and compelling evidence that potentially link the function of candidate genes to the neuroanatomic anomalies. A hypothesis has emerged in which impaired neuronal migration is a cellular neurobiological antecedent to RD. We critically evaluate the evidence for this hypothesis, highlight missing evidence, and outline future research efforts that will be required to develop a more complete cellular neurobiology of RD. © 2009 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . Neuroanatomy of RD . . . . . . . . . . . . . . . Ectopia. . . . . . . . . . . . . . . . . . . . Periventricular nodular heterotopia . . . . . . Malformation models and behavioral disruption Genetics of RD . . . . . . . . . . . . . . . . . . A brief history of RD genetics . . . . . . . . . Candidate gene for DYX1: DYX1C1 . . . . . . . Candidate genes for DYX2: KIAA0319 and DCDC2 Other candidate genes . . . . . . . . . . . . Functions of candidate genes . . . . . . . . . . . DYX1C1 . . . . . . . . . . . . . . . . . . . KIAA0319 . . . . . . . . . . . . . . . . . . DCDC2 . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

173 174 174 174 174 174 174 175 175 175 175 176 177 177 177 178 178

Introduction ⁎ Corresponding author. E-mail address: [email protected] (J.J. LoTurco). 1 These two authors contributed equally to the publication. Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2009.06.019

Reading Disability (RD) involves significant impairment of reading accuracy, speed and/or comprehension despite adequate intelligence and educational background (Katzir et al., 2006). Dyslexia presents with similar cognitive, neuroanatomical and genetic traits despite

174

L.A. Gabel et al. / Neurobiology of Disease 38 (2010) 173–180

additional spelling and writing impairments associated with reading disorder (RD), therefore for the purpose of this review dyslexia and RD are considered synonymous. RD is a phenotypically complex developmental disorder with a significant genetic component. As the most common learning disability (Lerner, 1989), affecting 5–12% of school aged children, RD has far-reaching social and economic consequences. Several cognitive and perceptual changes appear to associate with RD including changes in short-term memory (Kibby et al., 2004; Swanson et al., 2006), occulomotor skills (Frith and Frith, 1996; Rayner, 1998; Swanson et al., 2006), visuo-spatial abilities (Facoetti et al., 2009); sensory processing (Tallal, 1980; Tallal et al., 1993, 1980; Wright and Conlon, 2009), semantic encoding (Booth et al., 2007), integration of letter and speech sounds (Blau et al., 2009), and phonological processing (Habib, 2000; Ramus et al., 2003; Shaywitz et al., 1998). It remains controversial as to whether all of these features are central to the core RD phenotype, but the behavioral findings do suggest that any underlying cellular neurobiological cause of RD should have the capacity to affect multiple neural systems to varying degrees. Over the past several years, increased evidence for neuroanatomic changes in RD, identification of candidate genes, and elucidation of the functions of three candidate genes (KIAA0319, DCDC2 and DYX1C1) in neuronal migration have strengthened a hypothesis which states that impaired neuronal migration in development causes a predisposition to RD. We review the evidence for this hypothesis and highlight both the missing pieces and future research efforts that will be needed for a more complete cellular understanding of RD. Neuroanatomy of RD Neuroanatomical studies have revealed neurostructural correlates of RD. Postmortem studies were the first to support an association between cortical migration anomalies and RD, and animal models have supported a causal connection between cortical migrational anomalies and specific deficits in perception and learning. More recent imaging studies have found evidence of changes in grey and white matter that correlate with RD. Evidence, however, is still lacking from the absence of a large scale anatomical study, and it remains unclear whether the identified neuronal migration anomalies in postmortem studies are directly related to changes in neocortical structure or function that have been revealed in MRI studies. Ectopia Postmortem neuroanatomical examination of a relatively small sample of individuals with RD and controls revealed increases in the incidence of a focal neocortical abnormality known as neocortical “ectopia” in RD brains (Galaburda, 1988; Galaburda and Kemper, 1979; Galaburda et al., 1985). These layer 1 ectopia are generally too small for detection by MRI, and are present in most control brains studied although at a much lower rate of occurrence than in RD brains. Ectopia occur as a result of disrupted migration caused by either abnormal interactions between migrating neuroblasts and radial glial fibers and/or disruptions in the pia and layer I (Caviness et al., 1978; McBride and Kemper, 1982). The discovery of increased ectopia occurrence in RD was the first finding to suggest a connection between neuronal migration in the neocortex and RD. Periventricular nodular heterotopia Periventricular nodular heterotopia (PNH) are characterized by clusters of immature neurons partially embedded within the white matter near the surface of the lateral ventricles. This condition is most often caused by mutations in the x-linked gene filamin (Barkovich and Kuzniecky, 2000; Dubeau et al., 1995; Raymond et al., 1994), and loss of filamin function results in a failure of initial neuronal migration

from the precursor population that lines the lateral ventricles of the brain in fetal development. Studies combining in vivo imaging and behavioral assessments have shown an association between this cortical malformation type and RD (Chang et al., 2007, 2005). More specifically, PNH patients show processing deficits in real-word and non-word reading tasks (Chang et al., 2007). Moreover, the reading deficits in PNH patients were independent of intelligence, and the severity of reading disability amongst this group was found to correlate strongly with the amount of white matter disruption proximal to the PNH malformations (Chang et al., 2007). The white matter changes found in studies relating PNH to RD are consistent with a growing body of evidence for changes in white matter tracts reported in several studies comparing RD and control cases with diffusion tensor imaging (DTI) (Beaulieu et al., 2005; Deutsch et al., 2005; Klingberg et al., 2000; Niogi and McCandliss, 2006; Odegard et al., 2009; Steinbrink et al., 2008). Malformation models and behavioral disruption Animal models of the malformations have been used to test whether focal neocortical abnormalities can create behavioral and sensory deficits similar to some non-language based deficits correlated with RD. Ectopias virtually identical to those described in humans have been found in three strains of autoimmune mice (i.e. NZB/BlNJ, BXSB/MPJ and NXSM-D/Ei). Mice with neocortical ectopia are impaired in spatial and non-spatial working memory (Balogh et al., 1998; Boehm et al., 1996; Denenberg et al., 2001; Hoplight et al., 2001; Hyde et al., 2002), and in processing rapid auditory stimuli (Clark et al., 2000; Frenkel et al., 2000; Peiffer et al., 2001). Similarly, male rats with induced-microgyria in parietal cortex, a disruption in cortical lamination with similarities to and often associated with ectopia, display rapid auditory processing deficits (Clark et al., 2000; Fitch et al., 2008b; Herman et al., 1997) and working memory deficits (Fitch et al., 2008a). In all, the animal studies indicate importantly that even relatively small malformations in neocortical structure can have very specific effects on sensory and learning tasks without having large scale effects on general learning ability. Genetics of RD The current status of RD genetic association efforts, reviewed more thoroughly elsewhere (Gibson and Gruen, 2008; Paracchini et al., 2007), underscores the complexity of RD genetics. The composite evidence clearly shows a strong genetic risk; however, even the most consistently associated genetic loci and genes have not been significantly associated with RD in all sample populations. Moreover, there is no reported extended pedigree or large multigenerational family showing a specific mutation in the coding region of one of the three most replicated candidate genes. Similarly, RD risk haplotypes in all candidate genes to date are found in a significant percentage of individuals without RD. In spite of these caveats, the identification of three candidate genes (KIAA0319, DYX1C1 and DCDC2) has ushered in a new era of RD research that can begin to focus on molecular and cellular mechanisms. A brief history of RD genetics Familial cases of RD was noted as early as 1896 by W.P. Morgan, and since then the overall risk of RD within a family with an affected individual has been estimated at between 34% and 48% (Finucci et al., 1976; Gilger et al., 1991; Hallgren, 1950; Klasen, 1968; Zahalkova et al., 1972). A strong genetic component to this familial association was demonstrated by twin studies. The first twin studies carried out in the 1950s showed a monozygotic concordance for RD of 100% (Hallgren, 1950; Hermann, 1956; Hermann and Norrie, 1958), however this was revised down in later studies (Bakwin, 1973; Decker and Vandenberg,

L.A. Gabel et al. / Neurobiology of Disease 38 (2010) 173–180

175

Table 1

DYX1C1

KIAA0319

DCDC2

a b

Significant association

N

Nationality

No significant association

N

Nationality

Taipale et al. (2003)a Wigg et al. (2004)b Brkanac et al. (2007)b Dahdouh et al. (2009)b Francks et al. (2004)b Cope et al. (2005a)b Harold et al. (2006)b Meng et al. (2005a,b)b Schumacher et al. (2006)b Wilcke et al. (2009)a Ludwig et al. (2008)b

109 148 191 366 223 223 148 150 239 72 396

FIN CAN US GDR UK UK UK US GDR GDR GDR

Bellini et al. (2005)a Meng et al. (2005a,b)b Scerri et al. (2004)b Marino et al. (2004)b Brkanac et al. (2007)b

57 150 264 158 191

IT US UK IT US

Brkanac et al. (2007)b

191

US

Case control linkage disequilibrium. Family based transmission disequilibrium test.

1985; Stevenson et al., 1987), to a heritability between 29% and 82% (Alarcón and DeFries, 1997; DeFries et al., 1987; DeFries and Gillis, 1991; Harlaar et al., 2005; Hawke et al., 2006; Hohnen and Stevenson, 1999; LaBuda and DeFries, 1988; Pennington and Gilger, 1996). The large range of estimated heritability likely indicates that the genetic risk for RD is complex and modifiable by a variety of environmental influences operating within different sample populations. Genetic linkage disequilibrium analyses have now led to the identification of nine chromosomal loci across the genome that significantly associate with RD risk: DYX1–DYX9. Of these nine loci those located on chromosome 1p34–p36 (DYX8), 2p (DYX3), 6p21.3 (DYX2), and 15q21 (DYX1) have been frequently replicated, while those located at 3p12–q12 (DYX5), 6q13–q16 (DYX4), 11p15 (DYX7), 18p11 (DYX6), and Xq27 (DYX9) have been replicated once or not at all. Candidate susceptibility genes for DYX1 and DYX2, as well as other candidate genes are discussed below (see Table 1 for summary of recent findings). Candidate gene for DYX1: DYX1C1

larly orthographic sub-phenotypes (Cardon et al., 1994; Cardon et al., 1995; Fisher et al., 1999; Grigorenko et al., 2003; Grigorenko et al., 1997; Kaplan et al., 2002a,b; Smith et al., 1991). Two peaks of genetic association have been identified within DYX2 that include two candidate genes, KIAA0319 and DCDC2 (Kaplan et al., 2002a,b; Meng et al., 2005a). In 2002, Kaplan et al. showed a peak of association at a marker in the 5′ untranslated region of KIAA0319 (Kaplan et al., 2002a,b). In 2004 a study by Francks et al. showed a peak of association in a 77 kb region containing the first four exons of KIAA0319, and this was replicated by Cope et al. in 2005 using a dense set of SNPs to further identify a risk haplotype in the same region (Cope et al., 2005a). The risk haplotype was later shown to be related to a selective decrease in the expression of KIAA0319 but not other genes in the locus (Harold et al., 2006). The risk haplotype of KIAA0319 that includes the promoter region has more recently been shown to confer reduced promoter activity and an aberrant binding site for the transcriptional silencer OCT-1 (Dennis et al., 2009). Meng et al. (2005b) identified a deletion and compound short tandem repeat (STR) in intron 2 of DCDC2, a gene located 500 kb from KIAA0319. The STR in DCDC2 showed a significant association with RD in a cohort of 153 American dyslexic families (Meng et al., 2005b), and this association was independently confirmed in a German population (Schumacher et al., 2006). In this same association study in the German sample a haplotype within DCDC2 was identified that showed strength of association directly proportional to the severity of RD (Schumacher et al., 2006). More recently, the association between DCDC2 and RD has been independently confirmed in an Italian cohort, and the risk haplotype of DCDC2 associated with a decrease in enhancer activity (Meng et al., unpublished).

DYX1C1 was the first gene to be linked to RD when it was reported in 2000 that a chromosomal translocation involving 15q in two Finnish families with a history of RD caused a breakpoint within the DYX1 locus (Nopola-Hemmi et al., 2000; Nothen et al., 1999; SchulteKorne et al., 1998; Smith et al., 1983). Closer examination of the breakpoint showed that it disrupted exons of the gene EKN1, which was subsequently renamed Dyslexia Susceptibility 1 Candidate 1 (DYX1C1). Although this initial study showed a significant association in two relatively small Finnish samples (Taipale et al., 2003), several subsequent studies in populations in the UK, US, and Italy did not find a significant association (Cope et al., 2005b; Marino et al., 2005; Meng et al., 2005a). More recent studies of German and US samples, however, have shown that one of the RD-related single nucleotide polymorphisms (SNPs) in DYX1C1 does associate with RD (Brkanac et al., 2007; Dahdouh et al., 2009). In addition, a study of the same Italian sample in which a family based association between DYX1C1 risk alleles and RD was not found, did find a significant association with verbal short-term memory (Marino et al., 2007). Thus, DYX1C1 variants can associate with reading impairment in some population samples, and with component features often associated with RD in other samples (Marino et al., 2007). Finally, the DYX1C1 risk allele associated with RD appears to be functional in that there is a change in the 5′ promoter region that affects DNA interaction with a complex of proteins (TFII-I, PARP1, and SFPQ) that regulate gene expression (Tapia-Paez et al., 2008).

In addition to the three genes discussed above, candidate genes have also been identified in several other studies (Anthoni et al., 2007; Hannula-Jouppi et al., 2005; Poelmans et al., 2009); however, the genes identified in these studies have not yet been reported to associate with RD in larger populations. In 2005, FISH analysis of a translocation (t(3;8) (p12;q11)) in a Finnish RD individual revealed disruption between exons 1 and 2 of ROBO1 on 3p (Hannula-Jouppi et al., 2005). This gene lies within DYX5. Further linkage and association analysis of the proband's extended family revealed a SNP haplotype spanning the gene that showed marginal association with RD. ROBO1 and its ligand SLIT are well known to play roles in axonal targeting and also in cell migration. As such, ROBO1 is a compelling developmental candidate gene that may have direct effects on the development of axonal connections.

Candidate genes for DYX2: KIAA0319 and DCDC2

Functions of candidate genes

DYX2, on chromosome 6p, is the most replicated of DYX loci, and has been linked with both global and component RD phenotypes, particu-

The identification of candidate genes DYX1C1, KIAA0319 and DCDC2, presented a new opportunity to begin to test hypotheses

Other candidate genes

176

L.A. Gabel et al. / Neurobiology of Disease 38 (2010) 173–180

Fig. 1. Summary of RNAi studies demonstrating a role for Kiaa0319, Dcdc2, and Dyx1c1 in neuronal migration in the developing neocortex. (A) Example images of eGFP (green) labeled neurons in a patch of embryonic neocortex 4 days after four different manipulations. “Control” shows the normal dispersion pattern of neurons after they have migrated. “Kiaa0319”, “Dcdc2”, and “Dyx1c1” panels show the effects on cell dispersion and migration following RNAi knockdown of the indicated candidate gene. Note that in each condition the vast majority of cells fail to disperse by migration, and that each RNAi condition creates a somewhat distinct pattern. (B) A summary of RNAi results for both short-term and longterm effects of RNAi targeted against candidate genes (Burbridge et al., 2008; Meng et al., 2005b; Paracchini et al., 2006; Rosen et al., 2007; Wang et al., 2006). After 4 days of migration cells targeted with RNAi are largely stalled, but when examined in the adult brain the RNAi treatments caused a final phenotype that included normally positioned neurons, a mixture of heterotopia and ectopia, as well as scattered neuronal displacement. (C) Example of three types of malformations resulting from Dyx1c1 RNAi and examined in the mature rat brain: ectopia (small arrows), white matter heterotopia (open arrows) and hippocampal dysplasia (arrow points). In the lower panel transfected cells are labeled brown (Rosen et al., 2007).

with respect to potential cellular causes of RD. The association of RD with neuronal migration impairment discussed above led to a series of experiments to determine whether these candidate genes play a role in neuronal migration, and if so, to determine the types of malformations created by decreased expression of these genes (Burbridge et al., 2008; Meng et al., 2005b; Paracchini et al., 2006; Rosen et al., 2007; Threlkeld et al., 2007; Wang et al., 2006). Fig. 1 shows a summary of the results from these experiments. In this section we discuss the molecular features of three candidate genes as well as the studies that demonstrated their role in neuronal migration in developing neocortex. One limitation of the neuronal migration studies carried out so far is that they have directly tested for an involvement in migration in neocortex, and were not designed to test for changes in development of other structures or other developmental processes. Mouse knockout experiments are currently underway to test for a more general developmental role of these genes. The current evidence for a role in migration in neocortex should therefore not be viewed as evidence for a single specific function of the candidate genes in neuronal migration.

DYX1C1 The protein domains of DYX1C1 include an N-terminal p23 and three C-terminal tetratricopeptide repeat (TPR) domains. The Nterminal p23 domain of DYX1C1 protein, when overexpressed in cell lines, can interact with Hsp70, Hsp90 and an E-3 ubiquitin ligase, CHIP, suggesting that the protein may be involved in degradation of unfolded proteins (Hatakeyama et al., 2004). Recently, DYX1C1 has been shown to be involved in the degradation of the estrogen receptor potentially through its interaction with CHIP (Massinen et al., 2009). In vivo RNAi studies indicate that Dyx1c1 plays a role in neuronal migration in developing neocortex. Soon after transfection of a cohort of newly produced neurons with plasmids that induce RNAi or knockdown of Dyx1c1 expression, neurons become arrested in their normal migration path through the intermediate zone (Wang et al., 2006). Wang et al. 2006, went on to show that the TPR domains of Dyx1c1 were critical to migration in that mutations missing the TPR domains failed to rescue migration while expression of the TPR domains alone was sufficient to restore normal migration. Moreover, a

L.A. Gabel et al. / Neurobiology of Disease 38 (2010) 173–180

3 amino acid deletion in the last TPR domain which results from a SNP that was initially shown to associate with RD, but later not replicated in any other population, was found to be dispensable for Dyx1c1 function in neuronal migration in neocortex (Wang et al., 2006). In a follow-up study to the initial RNAi study, Rosen et al. (2007) examined what the final malformation profile would be for brains in which Dyx1c1 was knocked down. Although the embryo knockdown created a nearly uniform arrest in migration (Fig. 1A), most neurons restarted their migration and attained a position similar to control treated neurons by juvenile postnatal ages (Fig. 1B). However disruption of the laminar organization of the cortex was still evident in the Dyx1c1 knockdown condition compared to RNAi control group treated at same developmental stage. In addition, distinct malformation types were found to occur with some variety in different animals. These malformations included heterotopia in white mater, ectopia in layer one of neocortex, and hippocampal heterotopia with dysplasia. Behavioral assays of animals with Dyx1c1 RNAi induced malformations have also shown impairments in auditory processing and maze learning, and the changes in learning were correlated with the presence of the hippocampal heterotopia (Threlkeld et al., 2007). Cooccurrence of deep malformations such as white matter heterotopia with superficial malformations such as ectopia and microgyria have also been reported in certain human malformation syndromes (Wieck et al., 2005). Overall the experiments with Dyx1c1 knockdown have shown a surprising agreement with the neuronal migration hypothesis of RD. In particular the occurrence of diverse malformation types, including importantly ectopia (Fig. 1C), and complex behavioral outcomes following a genetic disruption, are reminiscent of the RD phenotype.

177

family, DCX, was identified by the discovery that mutations in DCX cause double cortex syndrome in females and lissencephaly in males (Barkovich and Kuzniecky, 2000; Gleeson et al., 1999). The dcx domain is critical for binding to and stabilizing microtubules and is regulated by phosphorylation (Gleeson et al., 1999). At least two members of this family, Dcx and Dclk, have now been found to interact genetically in mice in terms of growth of axons across the corpus callosum and in neuronal migration in cerebral cortex (Deuel et al., 2006; Koizumi et al., 2006). In a study comparing the biochemical and cellular functions of proteins in the Dcx family it was found that Dcdc2 exhibits the same functional features displayed by Dclk and Dcx protein (Coquelle et al., 2006). Based on the similarity of structure between Dcdc2 and Dcx proteins Meng et al. (2005b) hypothesized that DCDC2 may play a role in neuronal migration. Using an RNAi approach targeting Dcdc2 expression in migrating neocortical neurons in the embryonic rat neocortex it was found that knockdown of Dcdc2 interrupted neuronal migration (Meng et al., 2005b) (Fig. 1). More recently, Burbridge et al. (2008) has shown that the migration disruptions caused by knockdown of Dcdc2 results in diverse disruptions similar to but not identical to those created by Dyx1c1 knockdown (Burbridge et al., 2008). Knockdown of Dcdc2 creates both scattered heterotopia within the white matter similar to PNH, and also causes a population of neurons to over-migrate to ectopic positions in neocortex, although they do not form ectopia. The over-migration may be a secondary effect of migration delay because unlike the PNH “add back” or rescue experiments in which Dcdc2 is re-expressed resolved the PNH malformations, but did not eliminate the over-migration. Conclusions

KIAA0319 The KIAA0319 gene encodes an integral membrane protein with a large extracellular domain, a single transmembrane domain, and a small intracellular C-terminus. There are several splice variants of KIAA0319 (Velayos-Baeza et al., 2007), all of which are glycosylated, and one form is secreted (Velayos-Baeza et al., 2008). The extracellular domain is characterized by a consensus signal peptide, and 5 PKD domains. PKD domains in the polycytsin 1 protein have been shown to be involved in adhesion between kidney cells and so has been suggested as a cell adhesion domain (Silberberg et al., 2005). To date, there is only one defined protein interactor of KIAA0319 protein, adaptor protein-2 (AP-2), which is part of the endosomal pathway (Levecque et al., 2009). The structure, membrane localization, and emerging cell biology of KIAA0319 protein are consistent with it being in a relatively unstudied new class of neural cell adhesion molecule. KIAA0319 expression was targeted with RNAi in migrating neocortical neurons to test for a potential role in migration. Similar to Dyx1c1, RNAi knockdown of Kiaa0319 interrupted migration 4 days after transfection (Fig. 1) (Paracchini et al., 2006). Kiaa0319 knockdown, in contrast to knockdown of Dcdc2 and Kiaa0319, created a distinct cellular phenotype. Namely, disrupted neurons appeared to loose their normal radial association with radial glial fibers and migrating neurons were often found orthogonal to the radial glia scaffold that they typically migrate along (Paracchini et al., 2006). This phenotype, the emerging cell biology, and molecular structure of Kiaa0319 protein, suggest a possible role in neuron to radial glia adhesion; however, additional direct experimentation will be required to prove this role. DCDC2 DCDC2 is one of an eleven-member group of proteins distinguished by the presence of dcx or doublecortin domains (Coquelle et al., 2006; Reiner et al., 2006). The first characterized gene of this

Accumulating evidence is highly suggestive of a connection between disruptions in neuronal migration and genetic susceptibility to RD. It would be premature however at this point to conclude that RD is a disorder of neuronal migration. The changes in migration may be correlates of another function of these initially defined candidate genes, and the majority of the genetic risk for RD is not carried by KIAA0319, DCDC2, or DYX1C1. In addition, other potential functions of these three genes have not yet been thoroughly tested in genetic knockout experiments. In fact, all three of these candidate genes are expressed in mature neurons after migration, and may therefore have important functions in such processes as synaptic plasticity that would also affect learning. Enhanced genetic techniques and larger genome wide studies will be needed in the future to identify a larger fraction of the genetic risk and to determine more definitively the contribution of KIAA0319, DCDC2, and DYX1C1 risk alleles. Such studies will likely include association of copy number variations (CNV) in RD as has recently been shown successful in identifying candidate genes for autism and schizophrenia (Cantor and Geschwind, 2008; Glessner et al., 2009; Sebat et al., 2007). If RD does have a common underlying cause of neuronal migration impairment, then genes identified within such expanded searches would be expected to be genes that code for proteins involved in neuronal migration. Enhanced structural and functional imaging studies are needed to more clearly define the set of anatomical changes that associate most frequently with RD. Future studies should also include correlation between imaging and genetics. In particular it would be important to determine whether the candidate gene alleles correspond to specific morphological alterations. A recent preliminary study indicates a potentially promising beginning to this approach (Meda et al., 2008). Finally, the identification of a common neurodevelopmental disruption would only be the beginning of a mechanistic understanding of RD. Functional neurophysiological studies will be needed to connect any developmental disruption in neuronal positioning to changes in connectivity or function within cortical circuits. Work with

178

L.A. Gabel et al. / Neurobiology of Disease 38 (2010) 173–180

animal genetic models will most likely be required to define in detail the specific cellular neurophysiological disruptions following interruption of RD-related genes. There are already very effective educational interventions for RD that can greatly improve reading ability. Understanding the cellular basis of RD in detail in animal models could help to define critical periods of intervention, and may identify physiological mechanisms or changes that could be targeted pharmacologically to enhance early education-based remediation of RD. Acknowledgments Funding for CJG is from a Yale-Rosenberg Genetics Fellowship. Funding for JRG is provided by NIH R01 NS43530. Funding for JJL is provided by NIH R01HD. References Alarcón, M., DeFries, J.C., 1997. Reading performance and general cognitive ability in twins with reading difficulties and control pairs. Pers. Individ. Differ. 22, 793–803. Anthoni, H., Zucchelli, M., Matsson, H., Muller-Myhsok, B., Fransson, I., Schumacher, J., Massinen, S., Onkamo, P., Warnke, A., Griesemann, H., Hoffmann, P., Nopola-Hemmi, J., Lyytinen, H., Schulte-Korne, G., Kere, J., Nothen, M.M., Peyrard-Janvid, M., 2007. A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia. Hum. Mol. Genet. 16, 667–677. Bakwin, H., 1973. Reading disability in twins. Dev. Med. Child. Neurol. 15, 184–187. Balogh, S.A., Sherman, G.F., Hyde, L.A., Denenberg, V.H., 1998. Effects of neocortical ectopias upon the acquisition and retention of a non-spatial reference memory task in BXSB mice. Brain. Res. Dev. Brain Res. 111, 291–293. Barkovich, A.J., Kuzniecky, R.I., 2000. Gray matter heterotopia. Neurology 55, 1603–1608. Beaulieu, C., Plewes, C., Paulson, L.A., Roy, D., Snook, L., Concha, L., Phillips, L., 2005. Imaging brain connectivity in children with diverse reading ability. NeuroImage 25, 1266–1271. Bellini, G., Bravaccio, C., Calamoneri, F., Donatella Cocuzza, M., Fiorillo, P., Gagliano, A., Mazzone, D., del Giudice, E., Scuccimarra, G., Militerni, R., Pascotto, A., 2005. No evidence for association between dyslexia and DYX1C1 functional variants in a group of children and adolescents from Southern Italy. J. Mol. Neurosci. 27, 311–314. Blau, V., van Atteveldt, N., Ekkebus, M., Goebel, R., Blomert, L., 2009. Reduced neural integration of letters and speech sounds links phonological and reading deficits in adult dyslexia. Curr. Biol. 19, 503–508. Boehm, G.W., Sherman, G.F., Rosen, G.D., Galaburda, A.M., Denenberg, V.H., 1996. Neocortical ectopias in BXSB mice: effects upon reference and working memory systems. Cereb. Cortex 6, 696–700. Booth, J.R., Bebko, G., Burman, D.D., Bitan, T., 2007. Children with reading disorder show modality independent brain abnormalities during semantic tasks. Neuropsychologia 45, 775–783. Brkanac, Z., Chapman, N.H., Matsushita, M.M., Chun, L., Nielsen, K., Cochrane, E., Berninger, V.W., Wijsman, E.M., Raskind, W.H., 2007. Evaluation of candidate genes for DYX1 and DYX2 in families with dyslexia. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 144B, 556–560. Burbridge, T.J., Wang, Y., Volz, A.J., Peschansky, V.J., Lisann, L., Galaburda, A.M., Lo Turco, J.J., Rosen, G.D., 2008. Postnatal analysis of the effect of embryonic knockdown and overexpression of candidate dyslexia susceptibility gene homolog Dcdc2 in the rat. Neuroscience 152, 723–733. Cantor, R.M., Geschwind, D.H., 2008. Schizophrenia: genome, interrupted. Neuron 58, 165–167. Cardon, L.R., Smith, S.D., Fulker, D.W., Kimberling, W.J., Pennington, B.F., DeFries, J.C., 1994. Quantitative trait locus for reading disability on chromosome 6. Science 266, 276–279. Cardon, L.R., Smith, S.D., Fulker, D.W., Kimberling, W.J., Pennington, B.F., DeFries, J.C., 1995. Quantitative trait locus for reading disability: correction. Science 268, 1553. Caviness Jr., V.S., Evrard, P., Lyon, G., 1978. Radial neuronal assemblies, ectopia and necrosis of developing cortex: a case analysis. Acta Neuropathol. 41, 67–72. Chang, B.S., Ly, J., Appignani, B., Bodell, A., Apse, K.A., Ravenscroft, R.S., Sheen, V.L., Doherty, M.J., Hackney, D.B., O'Connor, M., Galaburda, A.M., Walsh, C.A., 2005. Reading impairment in the neuronal migration disorder of periventricular nodular heterotopia. Neurology 64, 799–803. Chang, B.S., Katzir, T., Liu, T., Corriveau, K., Barzillai, M., Apse, K.A., Bodell, A., Hackney, D., Alsop, D., Wong, S.T., Walsh, C.A., 2007. A structural basis for reading fluency: white matter defects in a genetic brain malformation. Neurology 69, 2146–2154. Clark, M.G., Rosen, G.D., Tallal, P., Fitch, R.H., 2000. Impaired processing of complex auditory stimuli in rats with induced cerebrocortical microgyria: an animal model of developmental language disabilities. J. Cogn. Neurosci. 12, 828–839. Cope, N., Harold, D., Hill, G., Moskvina, V., Stevenson, J., Holmans, P., Owen, M.J., O'Donovan, M.C., Williams, J., 2005a. Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia. Am. J. Hum. Genet. 76, 581–591. Cope, N.A., Hill, G., van den Bree, M., Harold, D., Moskvina, V., Green, E.K., Owen, M.J., Williams, J., O'Donovan, M.C., 2005b. No support for association between dyslexia susceptibility 1 candidate 1 and developmental dyslexia. Mol. Psychiatry 10, 237–238.

Coquelle, F.M., Levy, T., Bergmann, S., Wolf, S.G., Bar-El, D., Sapir, T., Brody, Y., Orr, I., Barkai, N., Eichele, G., Reiner, O., 2006. Common and divergent roles for members of the mouse DCX superfamily. Cell. Cycle 5, 976–983. Dahdouh, F., Anthoni, H., Tapia-Paez, I., Peyrard-Janvid, M., Schulte-Korne, G., Warnke, A., Remschmidt, H., Ziegler, A., Kere, J., Muller-Myhsok, B., Nothen, M.M., Schumacher, J., Zucchelli, M., 2009. Further evidence for DYX1C1 as a susceptibility factor for dyslexia. Psychiatr. Genet. Decker, S.N., Vandenberg, S.G., 1985. Colorado twin study of reading disability. In: Gray, DB, Kavanagh, JF (Eds.), Biobehavioural Measures of Dyslexia. York Press, Parkton, MD, pp. 123–135. DeFries, J.C., Gillis, J.J., 1991. Etiology of reading deficits in learning disabilities: quantitative genetic analysis. In: Obrzut, JE, Hynd, GW (Eds.), Neuropsychologocal Foundations of Learning Disabilities: A Handbook of Issues, Methods and Practice. Academic Press, Inc, London, pp. 29–47. DeFries, J.C., Fulker, D.W., LaBuda, M.C., 1987. Evidence for a genetic aetiology in reading disability of twins. Nature 329, 537–539. Denenberg, V.H., Hoplight, B., Sherman, G.F., Mobraaten, L.E., 2001. Effects of the uterine environment and neocortical ectopias upon behavior of BXSB-Yaa+mice. Dev. Psychobiol. 38, 154–163. Dennis, M.Y., Paracchini, S., Scerri, T.S., Prokunina-Olsson, L., Knight, J.C., Wade-Martins, R., Coggill, P., Beck, S., Green, E.D., Monaco, A.P., 2009. A common variant associated with dyslexia reduces expression of the KIAA0319 gene. PLoS Genet. 5, e1000436. Deuel, T.A., Liu, J.S., Corbo, J.C., Yoo, S.Y., Rorke-Adams, L.B., Walsh, C.A., 2006. Genetic interactions between doublecortin and doublecortin-like kinase in neuronal migration and axon outgrowth. Neuron 49, 41–53. Deutsch, G.K., Dougherty, R.F., Bammer, R., Siok, W.T., Gabrieli, J.D., Wandell, B., 2005. Children's reading performance is correlated with white matter structure measured by diffusion tensor imaging. Cortex 41, 354–363. Dubeau, F., Tampieri, D., Lee, N., Andermann, E., Carpenter, S., Leblanc, R., Olivier, A., Radtke, R., Villemure, J.G., Andermann, F., 1995. Periventricular and subcortical nodular heterotopia. A study of 33 patients. Brain 118 (Pt 5), 1273–1287. Facoetti, A., Trussardi, A.N., Ruffino, M., Lorusso, M.L., Cattaneo, C., Galli, R., Molteni, M., Zorzi, M., 2009. Multisensory spatial attention deficits are predictive of phonological decoding skills in developmental dyslexia. J. Cogn. Neurosci. Finucci, J.M., Guthrie, J.T., Childs, A.L., Abbey, H., Childs, B., 1976. The genetics of specific reading disability. Ann. Hum. Genet. 40, 1–23. Fisher, S.E., Marlow, A.J., Lamb, J., Maestrini, E., Williams, D.F., Richardson, A.J., Weeks, D. E., Stein, J.F., Monaco, A.P., 1999. A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia. Am. J. Hum. Genet. 64, 146–156. Fitch, R.H., Breslawski, H., Rosen, G.D., Chrobak, J.J., 2008a. Persistent spatial working memory deficits in rats with bilateral cortical microgyria. Behav. Brain Funct. 4, 45. Fitch, R.H., Threlkeld, S.W., McClure, M.M., Peiffer, A.M., 2008b. Use of a modified prepulse inhibition paradigm to assess complex auditory discrimination in rodents. Brain Res. Bull. 76, 1–7. Francks, C., Paracchini, S., Smith, S., Richardson, A., Scerri, T., Cardon, L., Marlow, A., MacPhie, I., Walter, J., Pennington, B., Fisher, S., Olson, R., DeFries, J., Stein, J., Monaco, A., 2004. 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. 75, 1046–1058. Frenkel, M., Sherman, G.F., Bashan, K.A., Galaburda, A.M., LoTurco, J.J., 2000. Neocortical ectopias are associated with attenuated neurophysiological responses to rapidly changing auditory stimuli. NeuroReport 11, 575–579. Frith, C., Frith, U., 1996. A biological marker for dyslexia. Nature 382, 19–20. Galaburda, A.M., 1988. The pathogenesis of childhood dyslexia. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 66, 127–137. Galaburda, A.M., Kemper, T.L., 1979. Cytoarchitectonic abnormalities in developmental dyslexia: a case study. Ann. Neurol. 6, 94–100. Galaburda, A.M., Sherman, G.F., Rosen, G.D., Aboitiz, F., Geschwind, N., 1985. Developmental dyslexia: four consecutive patients with cortical anomalies. Ann. Neurol. 18, 222–233. Gibson, C.J., Gruen, J.R., 2008. The human lexinome: genes of language and reading. J. Commun. Disord. 41, 409–420. Gilger, J.W., Pennington, B.F., DeFries, J.C., 1991. Risk for reading disability as a function of parental history in three family studies. Reading and Writing: An Interdisciplinary Journal 3, 205–217. Gleeson, J.G., Lin, P.T., Flanagan, L.A., Walsh, C.A., 1999. Doublecortin is a microtubuleassociated protein and is expressed widely by migrating neurons. Neuron 23, 257–271. Glessner, J.T., Wang, K., Cai, G., Korvatska, O., Kim, C.E., Wood, S., Zhang, H., Estes, A., Brune, C.W., Bradfield, J.P., Imielinski, M., Frackelton, E.C., Reichert, J., Crawford, E.L., Munson, J., Sleiman, P.M., Chiavacci, R., Annaiah, K., Thomas, K., Hou, C., Glaberson, W., Flory, J., Otieno, F., Garris, M., Soorya, L., Klei, L., Piven, J., Meyer, K.J., Anagnostou, E., Sakurai, T., Game, R.M., Rudd, D.S., Zurawiecki, D., McDougle, C.J., Davis, L.K., Miller, J., Posey, D.J., Michaels, S., Kolevzon, A., Silverman, J.M., Bernier, R., Levy, S.E., Schultz, R.T., Dawson, G., Owley, T., McMahon, W.M., Wassink, T.H., Sweeney, J.A., Nurnberger, J.I., Coon, H., Sutcliffe, J.S., Minshew, N.J., Grant, S.F., Bucan, M., Cook, E. H., Buxbaum, J.D., Devlin, B., Schellenberg, G.D., Hakonarson, H., 2009. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. Grigorenko, E.L., Wood, F.B., Meyer, M.S., Hart, L.A., Speed, W.C., Shuster, A., Pauls, D.L., 1997. Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15. Am. J. Hum. Genet. 60, 27–39. Grigorenko, E.L., Wood, F.B., Golovyan, L., Meyer, M., Romano, C., Pauls, D., 2003. Continuing the search for dyslexia genes on 6p. Am. J. Med. Genet., Part B (Neuropsychiatric. Genetics) 118B, 89–98.

L.A. Gabel et al. / Neurobiology of Disease 38 (2010) 173–180 Habib, M., 2000. The neurological basis of developmental dyslexia: an overview and working hypothesis. Brain 213 (Pt. 12), 2373–2399. Hallgren, B., 1950. Specific dyslexia (congenital word blindness). A clinical and genetic study. Acta Psychiatr. Neurol. Suppl. 65, 1–287. Hannula-Jouppi, K., Kaminen-Ahola, N., Taipale, M., Eklund, R., Nopola-Hemmi, J., Kaariainen, H., Kere, J., 2005. The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia. PLoS Genet. 1, e50. Harlaar, N., Spinath, F., Dale, P., Plomin, R., 2005. Genetic influences on early word recognition abilities and disabilities: a study of 7-year-old twins. J. Child Psychol. Psychiatry 46, 373–384. Harold, D., Paracchini, S., Scerri, T., Dennis, M., Cope, N., Hill, G., Moskvina, V., Walter, J., Richardson, A.J., Owen, M.J., Stein, J.F., Green, E.D., O'Donovan, M.C., Williams, J., Monaco, A.P., 2006. Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia. Mol. Psychiatry 11, 1085–1091 1061. Hatakeyama, S., Matsumoto, M., Yada, M., Nakayama, K.I., 2004. Interaction of U-boxtype ubiquitin–protein ligases (E3s) with molecular chaperones. Genes Cells 9, 533–548. Hawke, J.L., Wadsworth, S.J., DeFries, J.C., 2006. Genetic influences on reading difficulties in boys and girls: the Colorado twin study. Dyslexia 12, 21–29. Hermann, K., 1956. Congenital word blindness. Acta Psychiatr. Neurol. Scand. 108, 177–184. Hermann, K., Norrie, E., 1958. Is congenital word blindness a hereditary type of Gerstmann's syndrome? Psychiatr. Neurol. 136, 59–73. Herman, A.E., Galaburda, A.M., Fitch, R.H., Carter, A.R., Rosen, G.D., 1997. Cerebral microgyria, thalamic cell size and auditory temporal processing in male and female rats. Cereb. Cortex 7, 453–464. Hohnen, B., Stevenson, J., 1999. The structure of genetic influences on general cognitive, language, phonological, and reading abilities. Dev. Psychol. 35, 590–603. Hoplight, B.J., Sherman, G.F., Hyde, L.A., Denenberg, V.H., 2001. Effects of neocortical ectopias and environmental enrichment on Hebb–Williams maze learning in BXSB mice. Neurobiol. Learn. Mem. 76, 33–45. Hyde, L.A., Stavnezer, A.J., Bimonte, H.A., Sherman, G.F., Denenberg, V.H., 2002. Spatial and nonspatial Morris maze learning: impaired behavioral flexibility in mice with ectopias located in the prefrontal cortex. Behav. Brain Res. 133, 247–259. Kaplan, D., Gayán, J., Ahn, J., Won, T.W., Pauls, D., Olson, R., DeFries, J., Wood, F., Pennington, B., Page, G., Smith, S., Gruen, J., 2002a. Evidence for linkage and association with reading disability on 6p21.3-22. Am. J. Hum. Genet. 70, 1287–1298. Kaplan, D.E., Gayán, J., Ahn, J., Won, T.W., Pauls, D., Olson, R.K., DeFries, J.C., Wood, F., Pennington, B.F., Page, G.P., Smith, S.D., Gruen, J.R., 2002b. Evidence for linkage and association with reading disability, on 6p21.3-22. Am. J. Hum. Genet. 70, 1287–1298. Katzir, T., Kim, Y., Wolf, M., O'Brien, B., Kennedy, B., Lovett, M., Morris, R., 2006. Reading fluency: the whole is more than the parts. Annals of dyslexia 56, 51. Kibby, M.Y., Marks, W., Morgan, S., Long, C.J., 2004. Specific impairment in developmental reading disabilities: a working memory approach. J. Learn. Disabil. 37, 349–363. Klasen, 1968. Legasthenia. Huber, Bern. Klingberg, T., Hedehus, M., Temple, E., Salz, T., Gabrieli, J.D., Moseley, M.E., Poldrack, R.A., 2000. Microstructure of temporo-parietal white matter as a basis for reading ability: evidence from diffusion tensor magnetic resonance imaging. Neuron 25, 493–500. Koizumi, H., Tanaka, T., Gleeson, J.G., 2006. Doublecortin-like kinase functions with doublecortin to mediate fiber tract decussation and neuronal migration. Neuron 49, 55–66. LaBuda, M.C., DeFries, J.C., 1988. Genetic and environmental etiologies of reading disability: a twin study. Ann. Dyslexia 38, 131–138. Lerner, J.W., 1989. Educational interventions in learning disabilities. J. Am. Acad. Child. Adolesc. Psychiatry 28, 326–331. Levecque, C., Velayos-Baeza, A., Holloway, Z.G., Monaco, A.P., 2009. The dyslexiaassociated protein KIAA0319 interacts with Adaptor Protein 2 and follows the classical clathrin-mediated endocytosis pathway. Am. J. Physiol. Cell. Physiol. Ludwig, K., Schumacher, J., Schulte-Körne, G., König, I., Warnke, A., Plume, E., Anthoni, H., Peyrard-Janvid, M., Meng, H., Ziegler, A., Remschmidt, H., Kere, J., Gruen, J., Müller-Myhsok, B., Nöthen, M., Hoffmann, P., 2008. Investigation of the DCDC2 intron 2 deletion/compound short tandem repeat polymorphism in a large German dyslexia sample. Psychiatr. Genet. 18, 310–312. Marino, C., Giorda, R., Vanzin, L., Nobile, M., Lorusso, M., Baschirotto, C., Riva, L., Molteni, M., Battaglia, M., 2004. A locus on 15q15-15qter influences dyslexia: further support from a transmission/disequilibrium study in an Italian speaking population. J. Med. Genet. 41, 42–46. Marino, C., Giorda, R., Lorusso, M.L., Vanzin, L., Salandi, N., Nobile, M., Citterio, A., Beri, S., Crespi, V., Battaglia, M., Molteni, M., 2005. A family-based association study does not support DYX1C1 on 15q21.3 as a candidate gene in developmental dyslexia. Eur. J. Hum. Genet. 1–9. Marino, C., Citterio, A., Giorda, R., Facoetti, A., Menozzi, G., Vanzin, L., Lorusso, M.L., Nobile, M., Molteni, M., 2007. Association of short-term memory with a variant within DYX1C1 in developmental dyslexia. Genes Brain Behav. 6, 640–646. Massinen, S., Tammimies, K., Tapia-Paez, I., Matsson, H., Hokkanen, M.E., Soderberg, O., Landegren, U., Castren, E., Gustafsson, J.A., Treuter, E., Kere, J., 2009. Functional interaction of DYX1C1 with estrogen receptors suggests involvement of hormonal pathways in dyslexia. Hum. Mol. Genet. McBride, M.C., Kemper, T.L., 1982. Pathogenesis of four-layered microgyric cortex in man. Acta Neuropathol. 57, 93–98. Meda, S.A., Gelernter, J., Gruen, J.R., Calhoun, V.D., Meng, H., Cope, N.A., Pearlson, G.D., 2008. Polymorphism of DCDC2 reveals differences in cortical morphology of

179

healthy individuals — a preliminary voxel based morphometry study. Brain Imaging Behav. 2, 21–26. Meng, H., Hager, K., Held, M., Page, G.P., Olson, R.K., Pennington, B.F., DeFries, J.C., Smith, S.D., Gruen, J.R., 2005a. TDT-association analysis of EKN1 and dyslexia in a Colorado twin cohort. Hum. Genet. 118, 87–90. Meng, H., Smith, S.D., Hager, K., Held, M., Liu, J., Olson, R.K., Pennington, B.F., DeFries, J.C., Gelernter, J., O'Reilly-Pol, T., Somlo, S., Skudlarski, P., Shaywitz, S.E., Shaywitz, B.A., Marchione, K., Wang, Y., Paramasivam, M., LoTurco, J.J., Page, G.P., Gruen, J.R., 2005b. DCDC2 is associated with reading disability and modulates neuronal development in the brain. Proc. Natl. Acad. Sci. U. S. A. 102, 17053–17058. Niogi, S.N., McCandliss, B.D., 2006. Left lateralized white matter microstructure accounts for individual differences in reading ability and disability. Neuropsychologia 44, 2178–2188. Nopola-Hemmi, J., Taipale, M., Haltia, T., Lehesjoki, A.E., Voutilainen, A., Kere, J., 2000. Two translocations of chromosome 15q associated with dyslexia. J. Med. Genet. 37, 771–775. Nothen, M.M., Schulte-Korne, G., Grimm, T., Cichon, S., Vogt, I.R., Muller-Myhsok, B., Propping, P., Remschmidt, H., 1999. Genetic linkage analysis with dyslexia: evidence for linkage of spelling disability to chromosome 15. Eur. Child. Adolesc. Psychiatry 8, 56–59. Odegard, T.N., Farris, E.A., Ring, J., McColl, R., Black, J., 2009. Brain connectivity in nonreading impaired children and children diagnosed with developmental dyslexia. Neuropsychologia 47, 1972–1977. Paracchini, S., Thomas, A., Castro, S., Lai, C., Paramasivam, M., Wang, Y., Keating, B.J., Taylor, J.M., Hacking, D.F., Scerri, T., Francks, C., Richardson, A.J., Wade-Martins, R., Stein, J.F., Knight, J.C., Copp, A.J., Loturco, J., Monaco, A.P., 2006. The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration. Hum. Mol. Genet. 15, 1659–1666. Paracchini, S., Scerri, T., Monaco, A.P., 2007. The genetic lexicon of dyslexia. Annu. Rev. Genomics Hum. Genet. 8, 57–79. Peiffer, A.M., Dunleavy, C.K., Frenkel, M., Gabel, L.A., LoTurco, J.J., Rosen, G.D., Fitch, R.H., 2001. Impaired detection of variable duration embedded tones in ectopic NZB/BINJ mice. NeuroReport 12, 2875–2879. Pennington, B.F., Gilger, J.W., 1996. How is dyslexia transmitted. In: Chase, CH, Rosen, GD, Sherman, GF (Eds.), Developmental Dyslexia. Neural, Cognitive and Genetic Mechanisms. York Press, Baltimore, Maryland, pp. 41–61. Poelmans, G., Engelen, J.J., Van Lent-Albrechts, J., Smeets, H.J., Schoenmakers, E., Franke, B., Buitelaar, J.K., Wuisman-Frerker, M., Erens, W., Steyaert, J., Schrander-Stumpel, C., 2009. Identification of novel dyslexia candidate genes through the analysis of a chromosomal deletion. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 150B, 140–147. Ramus, F., Rosen, S., Dakin, S.C., Day, B.L., Castellote, J.M., White, S., Frith, U., 2003. Theories of developmental dyslexia: insights from a multiple case study of dyslexic adults. Brain 126, 841–865. Raymond, A.A., Fish, D.R., Stevens, J.M., Sisodiya, S.M., Alsanjari, N., Shorvon, S.D., 1994. Subependymal heterotopia: a distinct neuronal migration disorder associated with epilepsy. J. Neurol. Neurosurg. Psychiatry 57, 1195–1202. Rayner, K., 1998. Eye movements in reading and information processing: 20 years of research. Psychol. Bull. 124, 372–422. Reiner, O., Coquelle, F.M., Peter, B., Levy, T., Kaplan, A., Sapir, T., Orr, I., Barkai, N., Eichele, G., Bergmann, S., 2006. The evolving doublecortin (DCX) superfamily. BMC Genomics 7, 188. Rosen, G.D., Bai, J., Wang, Y., Fiondella, C.G., Threlkeld, S.W., LoTurco, J.J., Galaburda, A.M., 2007. Disruption of neuronal migration by RNAi of Dyx1c1 results in neocortical and hippocampal malformations. Cereb. Cortex 17, 2562–2572. Scerri, T., Fisher, S., Francks, C., MacPhie, I., Paracchini, S., Richardson, A., Stein, J., Monaco, A., 2004. Putative functional alleles of DYX1C1 are not associated with dyslexia susceptibility in a large sample of sibling pairs from the UK. J. Med. Genet. 41, 853–857. Schulte-Korne, G., Grimm, T., Nothen, M.M., Muller-Myhsok, B., Cichon, S., Vogt, I.R., Propping, P., Remschmidt, H., 1998. Evidence for linkage of spelling disability to chromosome 15. Am. J. Hum. Genet. 63, 279–282. Schumacher, J., Anthoni, H., Dahdouh, F., Konig, I.R., Hillmer, A.M., Kluck, N., Manthey, M., Plume, E., Warnke, A., Remschmidt, H., Hulsmann, J., Cichon, S., Lindgren, C.M., Propping, P., Zucchelli, M., Ziegler, A., Peyrard-Janvid, M., Schulte-Korne, G., Nothen, M.M., Kere, J., 2006. Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia. Am. J. Hum. Genet. 78, 52–62. Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y.H., Hicks, J., Spence, S.J., Lee, A.T., Puura, K., Lehtimaki, T., Ledbetter, D., Gregersen, P.K., Bregman, J., Sutcliffe, J.S., Jobanputra, V., Chung, W., Warburton, D., King, M.C., Skuse, D., Geschwind, D.H., Gilliam, T.C., Ye, K., Wigler, M., 2007. Strong association of de novo copy number mutations with autism. Science 316, 445–449. Shaywitz, S.E., Shaywitz, B.A., Pugh, K.R., Fulbright, R.K., Constable, R.T., Mencl, W.E., Shankweiler, D.P., Liberman, A.M., Skudlarski, P., Fletcher, J.M., Katz, L., Marchione, K.E., Lacadie, C., Gatenby, C., Gore, J.C., 1998. Functional disruption in the organization of the brain for reading in dyslexia. Proc. Natl. Acad. Sci. U. S. A. 95, 2636–2641. Silberberg, M., Charron, A.J., Bacallao, R., Wandinger-Ness, A., 2005. Mispolarization of desmosomal proteins and altered intercellular adhesion in autosomal dominant polycystic kidney disease. Am. J. Physiol. Renal. Physiol. 288, F1153–F1163. Smith, S.D., Kimberling, W.J., Pennington, B.F., Lubs, H.A., 1983. Specific reading disability: identification of an inherited form through linkage analysis. Science 219, 1345–1347. Smith, S.D., Kimberling, W.J., Pennington, B.F., 1991. Screening for multiple genes influencing dyslexia. Reading and Writing: An Interdisciplinary Journal 3, 285–298.

180

L.A. Gabel et al. / Neurobiology of Disease 38 (2010) 173–180

Steinbrink, C., Vogt, K., Kastrup, A., Muller, H.P., Juengling, F.D., Kassubek, J., Riecker, A., 2008. The contribution of white and gray matter differences to developmental dyslexia: insights from DTI and VBM at 3.0 T. Neuropsychologia 46, 3170–3178. Stevenson, J., Graham, P., Fredman, G., McLoughlin, V., 1987. A twin study of genetic influences on reading and spelling ability and disability. J. Child Psychol. Psychiatry 28, 229–247. Swanson, H.L., Howard, C.B., Saez, L., 2006. Do different components of working memory underlie different subgroups of reading disabilities? J. Learn. Disabil. 39, 252–269. Taipale, M., Kaminen, N., Nopola-Hemmi, J., Haltia, T., Myllyluoma, B., Lyytinen, H., Muller, K., Kaaranen, M., Lindsberg, P.J., Hannula-Jouppi, K., Kere, J., 2003. A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proc. Natl. Acad. Sci. U. S. A. 100, 11553–11558. Tallal, P., 1980. Auditory temporal perception, phonics, and reading disabilities in children. Brain Lang. 9, 182–198. Tallal, P., Stark, R.E., Kallman, C., Mellits, D., 1980. Developmental dysphasia: relation between acoustic processing deficits and verbal processing. Neuropsychologia 18, 273–284. Tallal, P., Miller, S., Fitch, R.H., 1993. Neurobiological basis of speech: a case for the preeminence of temporal processing. Ann. N. Y. Acad. Sci. 682, 27–47. Tapia-Paez, I., Tammimies, K., Massinen, S., Roy, A.L., Kere, J., 2008. The complex of TFII-I, PARP1, and SFPQ proteins regulates the DYX1C1 gene implicated in neuronal migration and dyslexia. FASEB J. 22, 3001–3009.

Threlkeld, S.W., McClure, M.M., Bai, J., Wang, Y., LoTurco, J.J., Rosen, G.D., Fitch, R.H., 2007. Developmental disruptions and behavioral impairments in rats following in utero RNAi of Dyx1c1. Brain Res. Bull. 71, 508–514. Velayos-Baeza, A., Toma, C., da Roza, S., Paracchini, S., Monaco, A.P., 2007. Alternative splicing in the dyslexia-associated gene KIAA0319. Mamm. Genome 18, 627–634. Velayos-Baeza, A., Toma, C., Paracchini, S., Monaco, A.P., 2008. The dyslexia-associated gene KIAA0319 encodes highly N- and O-glycosylated plasma membrane and secreted isoforms. Hum. Mol. Genet. 17, 859–871. Wang, Y., Paramasivam, M., Thomas, A., Bai, J., Kaminen-Ahola, N., Kere, J., Voskuil, J., Rosen, G.D., Galaburda, A.M., Loturco, J.J., 2006. DYX1C1 functions in neuronal migration in developing neocortex. Neuroscience 143, 515–522. Wieck, G., Leventer, R.J., Squier, W.M., Jansen, A., Andermann, E., Dubeau, F., Ramazzotti, A., Guerrini, R., Dobyns, W.B., 2005. Periventricular nodular heterotopia with overlying polymicrogyria. Brain 128, 2811–2821. Wilcke, A., Weissfuss, J., Kirsten, H., Wolfram, G., Boltze, J., Ahnert, P., 2009. The role of gene DCDC2 in German dyslexics. Ann Dyslexia 59, 1–11. Wigg, K., Couto, J., Feng, Y., Anderson, B., Cate-Carter, T., Macciardi, F., Tannock, R., Lovett, M., Humphries, T., Barr, C., 2004. Support for EKN1 as the susceptibility locus for dyslexia on 15q21. Mol. Psychiatry 9, 1111–1121. Wright, C.M., Conlon, E.G., 2009. Auditory and visual processing in children with dyslexia. Dev. Neuropsychol. 34, 330–355. Zahalkova, M., Vrzal, V., Kloboukova, E., 1972. Genetical investigations in dyslexia. J. Med. Genet. 9, 48–52.