Feature Review

A theoretical molecular network for dyslexia: integrating available genetic findings

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Abstract

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.

Introduction

Developmental dyslexia (or specific reading disability) is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in either intelligence, learning opportunity, motivation or sensory acuity. Dyslexia is the most common childhood learning disorder.1, 2, 3

The prevalence of dyslexia ranges from 3.6% in primary school children in The Netherlands4 to as high as 10% in US school-aged children,5 which is likely due to the fact that many different psychometric tests and diagnostic criteria for dyslexia exist (Box 1 ).2, 3, 6 Twice as many boys as girls are affected with dyslexia.4, 7, 8

Box 1: Diagnosis of dyslexia

Many different psychometric tests and diagnostic criteria for dyslexia exist. For a recent review of the different definitions and tests for dyslexia, we refer to Fletcher.6 Most of the linkage and association studies we refer to in this article make use of five measures of the normal reading process, that is single word reading (SWR), spelling, phoneme awareness (PA), phonological decoding (PD) and orthographic coding (OC).2, 3 Specific tests have been developed for each of these five reading measures2 and are used for the diagnosis of dyslexia. PA is the ability to reflect on and manipulate the phonemes of words. PD could be defined as the skill to convert written sublexical letter units (or graphemes) into their corresponding phonemes. The OC reading component reflects the ability to recognize the specific letter patterns (or orthography) of whole words. OC is a particularly important skill in English, in which frequently the same word sounds can be represented by different letter patterns.2 It should be noted that orthographic coding is less difficult in Dutch (or another ‘open’ language like German or Italian) than in English, as the Dutch language contains (much) less irregularities of grapheme to phoneme correspondences than exist in English.

Based on the five reading measures mentioned above, one commonly used scheme for diagnosing dyslexia uses cutoffs of a standard score of below −2 s.d. in children and a standard score of below −1.5 s.d. in adults for at least two of the five measures. Apart from frequent impairments in SWR and/or spelling, dyslexics usually show deficits in one or more of PA, PD and OC skills. Dyslexia should therefore be regarded as a continuum in which often, several measures of the normal reading process are affected to some extent. Moreover, the different reading measures seem to be (genetically) correlated with one another and with IQ.2, 3

Results from functional magnetic resonance imaging studies and studies using other functional brain imaging modalities (such as event-related potentials and magnetoencephalography), indicate that three regions in the left brain hemisphere are important for fluent reading (for recent reviews, see Shaywitz and Shaywitz9 and Hoskyn10). These regions are an ‘anterior’ system, that is the inferior frontal gyrus (Broca's area), and two ‘posterior’ systems, the dorsal parietotemporal and ventral occipitotemporal systems. Functional brain imaging studies have repeatedly demonstrated that dyslexic readers are characterized by a so-called ‘neural signature,’ in that the anterior system of their left brain hemisphere is slightly overactivated during reading tasks whereas, in contrast, the two posterior systems are underactivated.9, 10

Evidence from family and twin studies shows that dyslexia is a highly heritable disorder, and up to 75% of the phenotypic variance can be explained by genetic factors.2, 3, 4 Dyslexia behaves as a multifactorial (or complex) disorder, in which combinations of genetic and environmental factors contribute to disease risk. This article will concentrate on the genetic factors involved in dyslexia etiology. The genetic model underlying most cases of dyslexia is likely one in which several to multiple genetic factors, all of small or moderate individual effect size, contribute to disease risk.3, 5 In the current study, we reviewed the available evidence for dyslexia loci and genes, including linkage studies (candidate gene based) association studies and reports of chromosomal aberrations cosegregating with dyslexia. We found that 10 of the 14 dyslexia candidate genes that were suggested by the literature had been shown to directly or indirectly interact and could be integrated into a molecular signaling network contributing to dyslexia etiology, responsible for regulating neuronal migration and neurite outgrowth. Our work builds on findings of other researchers in the field of dyslexia genetics,5, 11, 12, 13 as well as existing knowledge about genes involved in neuronal migration disorders and the KEGG pathway for axon guidance (http://www.genome.jp/dbget-bin/show_pathway?map043600). Moreover, based on the signaling network, we propose three novel dyslexia candidate genes from linkage regions.

Linkage and association studies

As shown in Table 1, a substantial number of genetic linkage studies for developmental dyslexia have been carried out. At least 11 loci have been repeatedly linked to dyslexia and/or measures of the reading process known to be disturbed in dyslexia (Box 1), on chromosomes 1p35–1p36 (DYX8),14, 15, 16, 17, 18 2p11–2p16 (DYX3),2, 17, 19, 20, 21, 22, 23, 24 2q22.3,25, 26 3p12–3q13 (DYX5),2, 18, 27 6p22 (DYX2),1, 2, 18, 28, 29, 30 6q12–q15 (DYX4),31, 32 7q32,22, 31 11q13.4,25, 26 15q15–15q21 (DYX1),1, 18, 33, 34, 35, 36, 37 18p11.2 (DYX6)2, 31, 38 and Xq26–Xq28 (DYX9).2, 4, 18, 31 Additional (suggestive) linkage findings for chromosome regions 4p15.33–4p15.32,31 11p15.5 (DYX7),39 12q13.13–12q21.33,26 13q12.13–13q12.3,26 13q22.1,2 17p13.3,31 18q22.2–18q22.32 and 21q21–21q222 still await replication (Table 1). Considerable effort has been spent in trying to identify the dyslexia genes in a number of these regions by conducting candidate gene association studies, which will be discussed below and in Tables 2 and 3 . For additional reviews of the candidate gene association literature of dyslexia, we also refer to Petryshen and Pauls,5 Scerri and Schulte-Korne8 and Schumacher et al.40

Table 1: Linkage studies for developmental dyslexia and/or different measures of the reading process (Box 1)
Table 2: Reported associations of DYX1C1 at DYX1 with reading measures and dyslexia
Table 3: Reported associations of DCDC2, KIAA0319 and TTRAP at DYX2 with reading measures and dyslexia

Until now, no genome-wide association studies (GWAS) for developmental dyslexia have been published. However, Meaburn et al.41 reported a GWAS of early reading (dis)ability in the general population using a quantitative trait loci approach. In addition, the results of a GWAS for an electrophysiological endophenotype of dyslexia were reported.42

DYX1 locus (15q21)

Although located 7 Mb distal of the maximal linkage peak in the DYX1 locus,43, 44 the DYX1C1 gene was identified as the dyslexia candidate in the 15q21 locus. In 2003, Taipale et al.43, 45 reported the mapping of DYX1C1 from the breakpoint of a translocation (t(2;15)(q11;q21)) in four dyslexic members of an earlier described family. In the original article describing the mapping, nominally significant genetic association was also reported between alleles of two single nucleotide polymorphisms (SNPs) in the gene (rs3743205A and rs57809907T) and dyslexia. A haplotype of these two alleles was associated with dyslexia as well.43 However, efforts to replicate these original associations have produced mixed and sometimes conflicting results (Table 2). Four subsequent association studies failed to replicate an association of any allele of rs3743205 and rs57809907 with dyslexia,46, 47, 48, 49 whereas three other studies found a (nominally) significant association between dyslexia and/or specific reading measures and the opposite allele of rs374320550, 51 and/or rs57809907.50, 51, 52 One study reported association for the two-SNP haplotype that was reported in the original mapping study of DYX1C1,53 and more recently, a haplotype of three SNPs including rs3743205 was found associated with dyslexia in female probands.54 The (nominally) significant genetic association between the DYX1C1 missense variant rs17819126 and three reading and spelling measures was also reported55 (Table 2). Because of the above-described association results, several researchers in the dyslexia genetics field now submit that either another dyslexia candidate gene in DYX1 exists that remains to be discovered or that different causative variants in DYX1C1 might exist between different (language) populations.8, 56

Nevertheless, functional evidence points to DYX1C1 as a viable candidate for dyslexia etiology: DYX1C1 encodes DYX1C1 (alternative name: EKN1), a cytoplasmic and nuclear protein containing three tetratricopeptide repeat domains, known protein–protein interaction modules. DYX1C1 is expressed in several tissues, including the brain, where it localizes to cortical neurons and white matter glial cells.43, 57 In the promoter region of DYX1C1, a binding site for the ELK1 and TFII-I transcription factors is present.43 This binding site contains rs3743205,44 one of the SNPs associated with dyslexia in the original DYX1C1 study.43 Experiments in rats using in utero RNA interference against Dyx1c1 showed that the gene product has a role in neuronal migration (that is the migration of whole neurons to target regions during cerebral cortex development) in the developing neocortex. For this, the C-terminus of Dyx1c1 (which contains the three tetratricopeptide repeat domains) is necessary and sufficient.57 The neuronal migration anomalies resulting from the in utero RNA interference in rats appeared similar to those observed in a relatively small set (n=8) of post-mortem brains in humans with dyslexia (see Rosen et al.58 and references herein). Moreover, in rats, these neuronal migration anomalies were shown to lead to distinct impairments in auditory processing and spatial learning that have also been suggested to have a role in dyslexia.58, 59 Apart from its clear role in neuronal migration, several alternatively spliced transcript variants of DYX1C1 appear to be biomarkers for colorectal cancer.60 In addition, through one of its tetratricopeptide repeat domains, the DYX1C1 protein functions as a cochaperone by interacting with HSP70 (heat shock protein 70) and HSP90 (heat shock protein 90) proteins in breast cancer cells.61 Finally, in hippocampal neurons, DYX1C1 interacts with both the nuclear and cytoplasmic estrogen receptors α (ESR1) and β (ESR2)62 (see below). ESR1 and ESR2 have been recognized to be important in brain development and neuronal processes such as neuronal migration and synaptic plasticity.62 In addition, ERS1 and ERS2 are thought to be involved in cognitive processes such as learning and memory,62 which seem partially impaired in dyslexia.63

DYX2 locus (6p22)

A cluster of five genes at this locus (VMP, DCDC2, KIAA0319, TTRAP and THEM2) has been associated with dyslexia.30, 64 Of these five genes, genetic variants in DCDC2, KIAA0319 and TTRAP were reported to be associated with the disorder more than once3, 52, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 (Table 3).

In 2005, DCDC2 was identified as a dyslexia candidate gene in a fine mapping association study of the DYX2 locus.65 The study reported a 2445-bp deletion in intron 2 of DCDC2 that harbors a compound short tandem repeat polymorphism consisting of variable copy numbers of repeat units. Moreover, the combined allele of the deletion and minor alleles of the compound short tandem repeat marker (that is alleles with frequencies of <5%) yielded significant association with reading performance.65 However, a later association study failed to replicate this finding in a German dyslexia sample.66 Another study reported a haplotype consisting of specific alleles of two SNPs in intron 7 of DCDC2 (rs793862 and rs807701) to be associated with dyslexia67 (Table 3). In 2007, the 2445-bp deletion in intron 2 of DCDC2 was reported to be nominally associated with single word reading efficiency and spelling,52 and subsequently, healthy individuals heterozygous for the 2445-bp deletion were reported to exhibit significantly larger gray matter volumes in reading/language-related brain regions.68 More recently, the association findings for the intron 2 deletion as well as the two intron 7 SNPs were replicated in an independent case–control cohort.69 The same study also reported an association with dyslexia for another SNP, in intron 6 of DCDC2 (rs807724), and for a risk haplotype consisting of the deletion in DCDC2 and specific alleles of rs807724, rs793862 and rs807701.69 Very recently, two other intronic SNPs in DCDC2 (rs1419228 and rs1091047) were also reported to be associated with reading and spelling measures in a general population sample70 (Table 3).

DCDC2 is part of an 11-member doublecortin (DCX)-repeat gene family, including the DCX gene, which is involved in neuronal migration and mutated in X-linked lissencephaly and double cortex syndrome, two neuronal migration disorders.65, 78, 79 DCDC2 encodes a protein with two DCX domains. The known function of DCX domains is that they associate with, bundle and stabilize neuronal microtubules, which are essential for neurite outgrowth and neuronal migration.12, 13, 69, 78, 79, 80 The DCX domains are also ‘regulated’ through phosphorylation by MAP kinase proteins such as the extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2) proteins.80 DCDC2 is expressed in many organs and tissues, including the brain. Within the human brain, DCDC2 is expressed, among others, in regions that are implicated in reading ability.65, 78, 79, 81 Finally, as with DYX1C1 (see above), in utero RNA interference against the rat homolog of DCDC2 results in neuronal migration anomalies that are similar to those seen in a small set of post-mortem brains in humans with dyslexia (see Rosen et al.58 and references herein65, 81).

KIAA0319 was identified as a dyslexia candidate gene in two independent positional association studies of the 6p22 DYX2 locus.3, 71 Francks et al.3 identified a three-SNP risk haplotype consisting of specific alleles of two SNPs (rs4504469 and rs2038137) in KIAA0319 and rs2143340 in intron 2 of TTRAP that yielded association with several reading measures in UK and US samples of families with dyslexic individuals (Table 3). Association with rs4504469, rs203813771, 72 and the three-SNP risk haplotype73 was replicated in subsequent studies, whereas the rs2143340 SNP was also shown to be associated with normal variation in reading and spelling ability in the general population74 (Table 3). In addition, the risk haplotype containing rs2143340 was associated with >40% lower expression of KIAA0319 in lymphoblastoid cell lines from unaffected individuals and in neuroblastoma cell lines.75 Recently, an SNP in the promoter region of KIAA0319, rs9461045, that is in complete linkage disequilibrium with rs2143340 (and hence the risk haplotype for dyslexia) was shown to create a protein-binding site for the silencing transcription factor OCT-1.76 KIAA0319 expression from the risk haplotype increased upon small interfering (si-)RNA-mediated knockdown of the OCT-1 gene in a neuronal cell line, which implies that rs9461045 is the functional variant causing reduced expression of KIAA0319.76 Interestingly, nominally significant genetic interaction effects for the DCDC2 and KIAA0319 genes were reported and replicated, which suggests that both genes independently contribute to dyslexia risk.72, 77

KIAA0319 encodes a protein that consists of an extracellular part with a MANSC (motif at N-terminus with seven cysteines) domain and several overlapping fibronectin type III (FN III) and polycystic kidney disease (PKD) domains, a transmembrane domain and a cytoplasmic part (http://www.ensembl.org/homo_sapiens). Expression of KIAA0319 is specific to the brain, with highest levels in the cerebral cortex, hippocampus CA3 and dentate gyrus, putamen, amygdala and cerebellum of the adult human brain.75, 76, 82 PKD domains have been implicated in cell–cell adhesion processes, which led to the hypothesis that the KIAA0319 PKD domains have a role in the adhesion between neurons and glial fibers during neuronal migration.11, 13, 82

In utero RNA interference against the rat homolog of KIAA0319 indeed results in neuronal migration anomalies.75 Recently, embryonic knockdown of Kiaa0319 in rats was found to result in significant arrest of neuronal migration and subsequently causes specific types of neuronal migration anomalies in the postnatal rat brain whereas, in contrast, embryonic overexpression of Kiaa0319 does not cause gross neuronal migration anomalies.83 Lastly, apart from a main variant (variant A) of KIAA0319, two alternatively spliced products of the gene exist (variants B and C), which encode KIAA0319 isoforms that lack a transmembrane domain. Isoform B was found to be secreted, suggesting that KIAA0319 could be involved not only in cell–cell interactions, but also in extracellular signaling.82, 84

An additional putative dyslexia gene on 6p22 is TTRAP. As indicated above and in Table 3, rs2143340, an SNP in intron 2 of TTRAP, has yielded association with variation in spelling73 and reading73, 74 ability in the general population. Moreover, this SNP is a part of a three-SNP risk haplotype associated with dyslexia in studies of the KIAA0319 gene.3, 75 However, as the association findings for rs2143340 now seem to be due to its linkage disequilibrium with rs9461045 affecting the expression of KIAA031976 (see above), a role of TTRAP in dyslexia etiology has become unlikely.

The two other genes in the cluster of five genes at the DYX2 locus, that is VMP and THEM2, have not been repeatedly associated with developmental dyslexia.

DYX3 locus (2p11–p16)

In 2002, Francks et al.21 tested the SEMA4F and OTX1 genes in the DYX3 locus for association with dyslexia. SEMA4F belongs to a protein family with a role in axonal guidance, and the OTX1 protein is a transcription factor involved in forebrain morphogenesis and cortex differentiation.21 However, no association with dyslexia was found.21

In 2007, the C2ORF3 and MRPL19 genes were identified by positional candidate association mapping of the DYX3 locus,24 though these data still await replication. Both the C2ORF3 and MRPL19 genes are highly expressed in the adult and fetal human brain and although the function of both genes is unknown, it is interesting to note that C2ORF3 expression was found to correlate across brain regions with that of DYX1C1, DCDC2 and ROBO1, whereas MRPL19 expression was most highly correlated with the expression of KIAA0319.24

DYX5 locus (3p12–q13)

The ROBO1 gene was identified as the dyslexia candidate gene in this locus through its position at the 3p12 translocation breakpoint of an individual with dyslexia carrying a translocation between chromosomes 3 and 8 (t(3;8)(p12;q11)).85 Further examination of ROBO1 SNPs and haplotypes in a four-generation family determined that a haplotype cosegregated with dyslexia in 19 of 21 genotyped dyslexic family members.85 To date, there has been no independent replication of this finding.

The function of ROBO1—a gene that is highly expressed in the brain—in brain development and neuronal migration is well established. ROBO1 encodes a member of the ROBO family of axonal guidance receptors. ROBO1 and other ROBO family proteins consist of an extracellular part with five immunoglobulin (Ig) and three FN III domains, a transmembrane domain and a cytoplasmic part (http://www.ensembl.org/homo_sapiens). The ROBO (or Roundabout homolog) proteins are receptors for so-called SLIT proteins.

These interact with the netrin proteins and their receptor, DCC (deleted in colorectal carcinoma), to regulate the direction and rate of axon/neurite outgrowth85, 86 (see below).

DYX8 locus (1p35–p36)

So far, only one candidate gene in this locus was investigated. An association study of the KIAA0319L gene using five tagging SNPs in a Canadian sample of 291 nuclear families ascertained through a proband with reading difficulties found nominally significant evidence for association with dyslexia for one SNP (rs7523017; P=0.042) and a haplotype (P=0.032) in KIAA0319L in a subset of the sample (n=156 families).87 This finding still awaits replication.

KIAA0319L is expressed in several brain regions (http://biogps.gnf.org/#goto=genereport&id=79932) and although its function is still unknown, the gene has a high-protein sequence identity to KIAA0319 (http://www.ensembl.org/homo_sapiens), and may therefore have similar functions.

DYX9 locus (Xq26–Xq28)

This chromosome region contains 15 known protein-coding genes (http://www.ensembl.org/homo_sapiens), and due to their very high homology to the SLIT proteins88 that bind ROBO1 (see above), SLITRK2 and SLITRK4 in the region have been hypothesized to be dyslexia candidate genes.85 However, no mutations in the coding regions of these genes nor those of CXORF1 or FMR1, two other brain-expressed genes in the region, were identified in a family showing linkage to the DXS1227–DXS8091 region.4 That being said, the 5′ UTR trinucleotide repeat in FMR1, which—when expanded—leads to Fragile X syndrome, the most common inherited form of intellectual disability, was not investigated in this family. Fragile X syndrome is often accompanied by deficient reading skills.89 Moreover, 8 of 15 investigated females with fragile X syndrome and a normal intelligence were reported to have dyslexia,90 and males carrying a so-called FMR1 ‘premutation’—who are normally intelligent as well—display specific verbal working memory deficits91 often found to be present in dyslexics.63

FMR1 activates/phosphorylates the MAP kinase proteins ERK1 and ERK2 in hippocampal neurons.92 In addition, FMR1 acts as an RNA-binding protein involved in the localization and regulated translation of specific neuronal mRNAs encoding key molecules for neurodevelopmental processes such as synaptic plasticity and neurite outgrowth,93, 94, 95 including the mRNA of RAC1,96 a protein that has an important role in our putative dyslexia network (see below). Very recently, direct genetic interaction was also reported between the Drosophila homologs of the FMR1 and FLNA genes.97 The human FLNA gene encodes filamin A, a protein that directly binds and modulates the actin filaments in the neuronal cytoskeleton.95, 98 Mutations in FLNA cause periventricular nodular heterotopia type 1, a neuronal migration disorder that—apart from neurological symptoms such as epilepsy—has been associated with dyslexia in the context of a normal intelligence.99, 100

Chromosomal aberrations

Several chromosomal aberrations have been reported to cosegregate with dyslexia. As reported above, the DYX1C1 and ROBO1 genes in the DYX1 and DYX5 loci, respectively, were identified through their position in the breakpoints of translocations in dyslexic individuals.

Our own group recently reported PCNT, DIP2A, S100B and PRMT2 to be (partially) deleted in a small deletion of chromosome band 21q22.3 that cosegregated with dyslexia in a father and his three affected sons.56 Two of these genes seem valid candidate genes for dyslexia.

DIP2A encodes the ‘disco-interacting protein 2 homolog A’ (DIP2A).95 (In our original report,56 based on incorrect gene annotation information, we identified this gene as encoding the ‘DLX-interacting protein 2’, which is an alternatively spliced human variant of glutamate receptor interacting protein 1.101) The Drosophila homolog of DIP2A is involved in neuronal connectivity in the visual system.102 In humans, DIP2A is a nuclear protein that is ubiquitously expressed. In a complex with the transcription factors DMAP1,95, 103 DNMT1 and HDAC2,103 it negatively regulates neurite outgrowth104 and synaptic plasticity.105 Synaptic plasticity is crucial for cognitive processes such as learning and memory,105 which seem partially impaired in dyslexia (see above).63

The S100B gene is mainly and highly expressed in the brain (especially in the hippocampus).106 S100B encodes a calcium-binding peptide that is mainly produced by astrocytes and that exerts paracrine and autocrine effects on neurons and glial cells. S100B is known to bind to the receptor for advanced glycation end products (RAGE) protein in (hippocampal) neurons, which activates a signaling pathway resulting in neurite outgrowth.107 The protein has been reported to be involved in modulating synaptic plasticity,108 although the mechanism by which this is brought about is currently unknown.106 The concentration of the S100B peptide is increased in blood and cerebrospinal fluid in various clinical brain conditions, including psychiatric disorders such as schizophrenia and Tourette syndrome.106

In a very recent study, a microdeletion of the DOCK4 gene was found to cosegregate—though imperfectly—with dyslexia in individuals from two independent families in a study on rare structural DNA variants predisposing to autism and/or reading impairment/dyslexia.109

DOCK4 encodes a peripheral membrane protein95 that regulates dendritic growth and branching of hippocampal neurons110 and (neuronal) cell migration111 through the activation of RAC1.

A deletion of chromosome 7q11.23 results in Williams–Beuren syndrome (WBS), a human neurodevelopmental syndrome that has multisystemic manifestations including mild-to-moderate mental retardation and cognitive deficits. WBS has also been associated with reading difficulties and ‘full’ dyslexia.112, 113, 114 The deletion of GTF2I as part of the WBS deletion is responsible for the rather typical neurocognitive profile associated with WBS and, more specifically, for the visuospatial construction deficits that are very often seen in individuals with WBS.115, 116 Visuospatial construction deficits are also found in people with dyslexia.117 Another indication that GTF2I is involved in the etiology of language-related disorders is the fact that in a recent study of people with a 7q11.23 microduplication syndrome involving GTF2I, all 13 subjects investigated in the study also had some degree of specific language impairment,118 a disorder that is comorbid with dyslexia.8 In these individuals, the expression of only two genes in the duplicated region was upregulated, that is GTF2I and CYLN2.118 Interestingly, mice with haploinsufficiency for Cyln2, the other gene that was upregulated in the duplicated region, have features of WBS, including mild growth deficiency and deficits in motor coordination.119 GTF2I is highly expressed in the brain, where it has a role in normal brain development. It encodes the transcription factor TFII-I.44 As indicated above, TFII-I binds to the promoter of the DYX1C1 gene at a binding site containing rs3743205,44 the SNP associated with dyslexia.43, 50, 51, 53, 54 TFII-I acts as an enhancer or suppressor of the transcription of DYX1C1 depending on the context of other transcription factors.44

From single candidate genes to an integrated molecular network

As discussed earlier, 14 genes from the literature had (at least some) evidence for involvement in the etiology of dyslexia, that is DYX1C1, DCDC2, KIAA0319, C2ORF3, MRPL19, ROBO1, KIAA0319L, FMR1, PCNT, DIP2A, S100B, PRMT2, DOCK4 and GTF2I. An analysis with the GOstat bioinformatics tool (http://gostat.wehi.edu.au/)120 showed that after correction for multiple testing, 6 of the 10 most significantly enriched gene ontology terms in these 14 candidate genes are related to nervous system development in general and/or neurite outgrowth in particular, that is generation of neurons, neurogenesis, axonogenesis, neuron projection morphogenesis, neuron projection development and neuron development (Table 4 ). Whereas three genes from the set carried gene ontology terms implicating them in neurite outgrowth (that is DCDC2, ROBO1 and S100B), it was clear from the above review that more genes could be linked to this process and the related neurodevelopmental process of neuronal migration.

Table 4: Top 10 gene ontology (GO) terms significantly enriched in the 14 dyslexia candidate genes from the literature using the GOstat bioinformatics tool (http://gostat.wehi.edu.au/120

Therefore, we systematically searched PubMed (http://www.ncbi.nlm.nih.gov/sites/entrez) and the Uniprot Protein Knowledgebase (http://www.uniprot.org/uniprot)95 for the (proposed) function of the proteins that are encoded by the 14 dyslexia candidate genes that were described above.

As shown and described in (the legends of) Figures 1 and 2, 10 of the 14 proposed dyslexia candidate genes (that is ROBO1, KIAA0319, KIAA0319L, S100B, DOCK4, FMR1, DIP2A, GTF2I, DYX1C1 and DCDC2) fit into a neurodevelopmental and theoretical molecular network. All the corresponding proteins could be directly or indirectly linked to processes regulating and modulating cytoskeletal microtubules and actin filaments that are involved in neuronal migration and/or the directed outgrowth of neurites/axons. The proposed network therefore fits and extends the currently dominating hypothesis of dyslexia as a neuronal migration disorder.5, 11, 12, 13, 57, 58, 59, 65, 75, 81, 82, 83

Figure 1
Figure 1

Schematic representation of the dyslexia molecular signaling network for neurite outgrowth and neuronal migration. The color code we have used in Figures 1 and 2 to indicate the level of evidence that implicates the dyslexia candidate genes/proteins in the etiology of dyslexia is described in more detail in the article text. In short, the orange proteins are encoded by genes for which there is relatively robust evidence. The yellow proteins represent genes for which we found less robust evidence, and the purple proteins are encoded by genes we proposed as dyslexia candidates based on their location in dyslexia linkage regions. SLIT and Netrin axonal guidance pathways at the neuronal cell membrane regulate the CDC42-extracellular signal-regulated kinase (ERK)1/2 cascade (a). This process is shown and described in more detail in (the legend of) Figure 2. Binding of S100B and HMGB1 to receptor for advanced glycation end product (RAGE) results in CDC42135 and ERK1/2132 activation (b). The latter is also induced by FMR1.92 DOCK4,110 S100B and HMGB1 binding to RAGE136, 137 activate RAC1 (b), which in turn activates the transcriptional activity of NF-κB136 (c). FMR1 also activates ERK1 and ERK292 (d, e) and it is involved in the translation of the mRNA of RAC196 (d). Activated ERK1 and ERK2 (also) activate/phosphorylate the NF-κB,138 ETS1,139 ELK1140 and TFII-I141 transcription factors (c). ERK1 and ERK2 also activate/regulate DCDC280 (e). Activated NF-κB upregulates the transcription and expression of Netrin-1 (NTN1)142 and HSP90.143 It also upregulates the transcription of ELK1,144 a transcriptional activator of DYX1C1.43 ETS1 regulates the transcription of SLIT3129 and is directly activated by HMGB1128 (c). Activated (nuclear) TFII-I141 upregulates or downregulates the transcription of DYX1C1, depending on the context of other transcription factors.43, 44 DIP2A binds DMAP1,102 which itself is a part of the DMAP1–DNMT1–HDAC2 repressive transcription complex.103 HDAC2 inhibits ELK195 and ESR1, the nuclear estrogen receptor α145 (c). When bound by their endogenous ligand 17β-estradiol, the nuclear ESR1 and ESR2 (estrogen receptor β) proteins—which form heterodimers—upregulate the expression of reporter genes containing estrogen response elements (ERE) by directly binding to the DNA sequences containing these ERE95 (c). This process is enhanced—for ESR1—by HMGB1130 and suppressed—for both ESR1 and ESR2—by DYX1C1.62 DYX1C1 also binds directly to nuclear ESR1 and ESR2, which promotes their proteosomal degradation62 (c). ESR1 and ESR2 are also found in the cytoplasm, where they are involved in activating ERK1/262, 146 (d). The ESR–DYX1C1 complexes that promote the proteosomal degradation of ESR1 and ESR2 are also found in the cytoplasm,62 and we hypothesize that a complex of VAPA,122 HSP90 and DYX1C161 would be involved in degrading cytoplasmic ESR1 and ESR2 (d). Lastly, activated DCDC2 as well as FLNA directly bind and modulate neuronal microtubules and actin filaments65, 69, 78, 79, 80, 81, 95, 98 (e). HSP90, heat shock protein 90; NF-κB, nuclear factor kappa-B; VAPA, VAMP-associated protein A.

Figure 2
Figure 2

Schematic representation of how the proteins from the Netrin and SLIT molecular guidance pathways interact to regulate the direction and rate of axon/neurite outgrowth. The color code we have used in Figures 1 and 2 to indicate the level of evidence that implicates the dyslexia candidate genes/proteins in the etiology of dyslexia is described in detail in the article text. In short, the orange proteins are encoded by genes for which there is relatively robust evidence. The yellow proteins represent genes for which we found less robust evidence, and the purple proteins are encoded by genes we proposed as dyslexia candidates based on their location in dyslexia linkage regions. In a simplified model of the interaction between the SLIT and Netrin ligands with their receptors, Netrin-1 binding to the DCC (deleted in colorectal carcinoma) receptor leads to the activation of CDC42,131 which in turn phosphorylates and activates the cytoplasmic Extracellular signal-regulated kinase (ERK) 1 and 2 proteins 132 (2). The activation of ERK1 and ERK2 leads to further downstream signaling through different second messenger systems resulting in changes in the cytoskeletal organization of microtubules and actin filaments. This, in turn, results in neurite attraction towards the netrin guidance cues and stimulation of neurite outgrowth.86 However, when both ROBO1 and DCC receptors are present in the neuronal plasma membrane (1), the binding of Netrin-1 to DCC still leads to the activation of CDC42 and subsequently of ERK1/2, but SLIT(2) binding to one of the immunoglobulin (Ig) domains of the ROBO1 receptor86 results in the cytoplasmic domains of ROBO1 and DCC interacting86 and in binding of an srGAP protein to the cytoplasmic domain of ROBO1. This in turn reduces/inhibits the activity of CDC42.133, 134 The end result of the interaction between ROBO1 and DCC is still stimulation of neurite outgrowth, but the neurite attraction towards the Netrin guidance cues is silenced.86 When only a ROBO1 receptor is present in the neuronal plasma membrane (3), binding of SLIT(2) to one of the Ig domains of the ROBO1 receptor86 eventually leads—through the inhibition of CDC42—to stimulation of neurite outgrowth but repulsion away from the SLIT guidance cues.86, 126, 133, 134

In addition to the 14 candidate genes described above, the delineation of the molecular network enabled us to propose three additional dyslexia candidate genes from linkage regions in which no candidates had been described thus far.

In the DYX6 locus on 18p11.2, marker D18S464—which showed genetic linkage with (single word) reading in two dyslexia linkage studies2, 31 (Table 1)—is located immediately downstream from the VAPA gene, in a linkage disequilibrium block that contains part of the VAPA gene (http://www.broad.mit.edu/mpg/haploview/). The VAPA gene is highly expressed in the brain.

The VAPA protein (other names: VAP-33 or VAMP-associated protein A) is an integral membrane protein found in the (neuronal) cell membrane, membranes of cellular organelles (such as the Golgi apparatus) and associated with microtubules.121, 122 VAPA was reported to have an important role in stimulating neurite outgrowth.123 In addition, it is involved in synaptic plasticity124 and necessary for vesicular neurotransmission at the synapse.121, 122, 125 Like DYX1C1,61 VAPA binds and forms a complex with HSP90, a protein with many functions including a role in intracellular vesicle transport.122 Recently, genetic association between several SNPs in VAPA and bipolar disorder has been reported.125

Suggestive genetic linkage of ‘irregular word spelling’ near marker D4S2633 on chromosome 4p15.32 was reported in the dyslexia linkage study by Bates et al.31 (Table 1). The gene nearest to this marker is SLIT2, which maps 1.3 Mb proximally. SLIT2 encodes a ligand of the ROBO family of axonal guidance receptors of which the dyslexia candidate ROBO1 is a member.86, 126

In the study by Igo et al.,26 linkage with ‘single word reading efficiency’ was reported for marker ATA5A09 on 13q12.3 (Table 1). ATA5A09 is located within the HMGB1 gene (http://www.ensembl.org/homo_sapiens). Like S100B, the encoded protein (HMGB1 or Amphoterin) binds to the RAGE receptor and is involved in neurite outgrowth.107, 127

HMGB1 can also directly activate the ETS1 transcription factor,128 which upregulates another SLIT gene, that is SLIT3.129 In addition, HMGB1 enhances the ESR1-induced expression of genes containing estrogen response elements130 (see below).

In Figures 1 and 2, we have used a color code indicating the level of ‘evidence’ that implicates the above-described/proposed dyslexia candidates in the etiology of dyslexia. Proteins with relatively robust evidence for involvement in dyslexia are indicated in orange. These proteins are encoded by genes that were disrupted by translocation breakpoints in dyslexic individuals (DYX1C1 and ROBO1) and/or found associated with dyslexia, requiring repeated association findings for those genes not implicated by translocations (DYX1C1, DCDC2, KIAA0319 and ROBO1). Indicated in yellow are proteins with less robust evidence of their involvement in dyslexia. These proteins are encoded by genes that were repeatedly found to be deleted in people with dyslexia (PCNT, DIP2A, S100B, PRMT2, GTF2I and DOCK4), genes that showed (nominal) association with dyslexia in only one study (C2ORF3, MRPL19 and KIAA0319L) and FMR1 that was mutated in people with dyslexia. The proteins indicated in purple are encoded by the three novel dyslexia candidate genes we propose based on their location in reported dyslexia linkage regions (VAPA, SLIT2 and HMGB1).

Signaling through the network can be initiated at the neuronal cell membrane by the interacting SLIT and netrin axonal guidance pathways, which regulate the direction and rate of axon/neurite outgrowth (Figures 1a and 2). The molecular guidance ‘cues’ SLIT (including the dyslexia candidate SLIT2) and Netrin (mainly the Netrin-1 protein) bind to ROBO1 and DCC, respectively.86, 126 As shown and described in more detail in (the legend of) Figure 2, the rate and direction of outgrowth is critically dependent on the exact receptor composition in the plasma membrane. As they have fibronectin type III domains very similar to those of the DCC receptor protein (http://www.ensembl.org/homo_sapiens), the KIAA0319 and KIAA0319L proteins may function as receptors for netrin-like molecules. However, these interactions are hypothetical and have not yet been confirmed by experimental data, and therefore are not shown in Figures 1 and 2. Moreover, as suggested by others, KIAA0319,11, 13, 82 and possibly KIAA0319L, might alternatively/additionally function in the direct adhesion between neurons and glial fibers during neuronal migration through their polycystic kidney disease domains.

As indicated in Figure 2, the activation of the ROBO1 and DCC receptors leads to signaling via CDC42131 and cytoplasmic ERK1 and ERK2 proteins132 resulting in changes in the cytoskeletal organization of microtubules and actin filaments and (eventually) in neurite outgrowth.86, 126, 133, 134 Two other dyslexia candidates, S100B and HMGB1, can also result in CDC42135 and ERK1/2132 activation and neurite outgrowth by binding to RAGE106, 127 (Figure 1b). In addition, S100B or HMGB1 binding to RAGE also activates RAC1136, 137 (Figure 1b). This latter pathway is also activated by DOCK4, a peripheral membrane protein95 that regulates dendritic growth and branching of hippocampal neurons110 (Figure 1b). In the cytoplasm of hippocampal neurons, FMR1 also activates ERK1 and ERK292 (Figures 1d and e). Moreover, FMR1 is involved in the translation of the mRNA of RAC196 (Figure 1d).

Activated ERK1 and ERK2 activate/phosphorylate the NF-κB (nuclear factor kappa-B),138 ETS1,139 ELK1140 and TFII-I141 transcription factors (Figure 1c). NF-κB is also activated downstream of RAC1.136 All four transcription factors seem to have a role in the dyslexia neurodevelopmental network. Activated NF-κB upregulates the transcription of the Netrin-1142 and HSP90143 genes. It also upregulates the transcription of the ELK1 gene,144 a transcriptional activator of DYX1C1.43 ELK1 is a brain-expressed transcription factor, and its activation has been associated with neurite outgrowth and hippocampus-dependent learning in rats.43 The ETS1 transcription factor regulates the transcription and expression of the SLIT3 gene.129 Activated (nuclear) TFII-I141 upregulates or downregulates the transcription and expression of the DYX1C1 gene, depending on the context of other transcription factors.43, 44

The nuclear protein DIP2A binds DMAP1,102 which is a part of the DMAP1–DNMT1–HDAC2 repressive transcription complex103 (Figure 1c). HDAC2—through which the DMAP1–DNMT1–HDAC2 complex negatively regulates neurite outgrowth104—is involved in repressing the transcriptional activity of ELK1,95 which results in a reduced expression of DYX1C1. HDAC2 also directly inhibits ESR1, the nuclear estrogen receptor α.145

The nuclear ESR1 and ESR2 proteins—when activated—upregulate the expression of genes containing estrogen response elements by directly binding to the DNA sequences containing these elements95 (Figure 1c). This process—that is important in brain development and neuronal processes such as neuronal migration and synaptic plasticity62 (see above)—is enhanced—for ESR1—by HMGB1130 and suppressed—for both ESR1 and ESR2—by DYX1C1.62 DYX1C1 also binds directly to nuclear ESR1 and ESR2, which promotes their proteosomal degradation and hence negatively regulates the function of these proteins.62

In addition to their role in the cell nucleus, ESR1 and ESR2 are also found in the cytoplasm of hippocampal neurites, where they are involved in activating ERK1/262, 146 (Figure 1d). The ESR–DYX1C1 complexes that promote the proteosomal degradation of ESR1 and ESR2 are also found in the cytoplasm of hippocampal neurites (Figure 1d), which suggests the involvement of DYX1C1 in negatively regulating estrogen signaling cascades in these neurites.62 Moreover, as both DYX1C161 and VAPA122 bind to HSP90, this makes one speculate that a complex of VAPA, HSP90 and DYX1C1 would be involved in degrading and negatively regulating cytoplasmic ESR1 and ESR2 (Figure 1d).

After being activated by any of the above-described cascades, the ERK1/2 proteins also regulate the activity of the DCDC2 protein by phosphorylating its DCX domains80 (Figure 1e). DCDC2 and FLNA—a protein that is encoded by a gene interacting with FMR197 (see above)—directly bind and modulate neuronal microtubules and actin filaments that are involved in neurite outgrowth and neuronal migration11, 12, 13, 65, 69, 78, 79, 80, 81, 95, 98, 99, 100 (Figure 1e).

As already stated above, two GWAS related to reading disability have been reported to date. The first was a GWAS using a quantitative trait loci approach comparing the two extremes of the reading ability spectrum of the normal population in 1502 children from the UK Twins Early Development Study TEDS.41 The authors used a pooled design and SNP arrays of only 100.000 SNPs, which greatly reduced the power of the study. Nevertheless, they nominally replicated some of their findings in 4258 additional samples from TEDS, resulting in 10 SNPs of interest for reading ability in early childhood.41 Six of these SNPs are located in introns of protein-coding genes (http://www.ensembl.org/homo_sapiens), three of which could be directly linked to our molecular network for dyslexia: CDC42BPA (rs1320490; P=0.030), TIAM1 (rs2409411; P=0.004) and DPF3 (rs2192595; P=0.003).41 CDC42BPA is a downstream effector of CDC42 involved in modulating the neuronal cytoskeleton95 and hence neurite outgrowth.12 TIAM1 is a cytoplasmic protein that is involved in neurite outgrowth by directly activating RAC1.147 DPF3 is a nuclear protein that belongs to the neuron-specific chromatin remodeling complex (also called the nBAF complex),95 which has an important role in neural development and dendritic outgrowth of neurons.148

Recently, the results of a GWAS for an electrophysiological endophenotype of dyslexia (that is the so-called ‘mismatch negativity component’ or MMN) in a discovery sample of 200 and a replication sample of 186 dyslexic children were reported.42 Genome-wide significance was reached for two SNPs in high linkage disequilibrium in CLSTN2 (rs1365152 and rs2114167) in the discovery sample, though this finding was not replicated. As the replication sample was less strongly affected with dyslexia than the discovery sample, the authors suggest that CLSTN2 should not yet be discarded as a dyslexia candidate.42 The gene encodes calsyntenin 2, a brain-specific protein localizing to postsynaptic specializations of asymmetric synapses in the adult mouse brain149 and shows association with verbal working memory,150 a cognitive process that is repeatedly found to be impaired in dyslexic subjects.42, 63

Although its function is currently unknown, in analogy with its homologue calsyntenin 1,151 CLSTN2 might have a role in axonal transport, and may therefore fit well into our proposed neuronal migration and neurite outgrowth network.

In addition to the finding in CLSTN2, genome-wide significant association was reported in the combined discovery and replication sample between the late component of the MMN and rs4234898 on 4q32.1, an SNP in a gene desert, that ‘trans-regulates’ the expression of SLC2A3 (other name: GLUT3) on 12p13.31. SLC2A3 encodes the predominant facilitative glucose transporter in the brain. Therefore, the authors suggest that the ‘trans-regulation’ effect of rs4234898 (and a haplotype of this SNP with rs11100040) on SLC2A3 might lead to decreased glucose uptake in dyslexic children that could in turn explain their attenuated MMN results.42 The expression of the SLC2A3 gene is known to be upregulated by NF-κB152 and through estradiol/ESR1 activation.153 Moreover (glutamatargic) excitation of the neuronal cell membrane causes a translocation of SLC2A3 to the cell membrane leading to increased glucose uptake,154 which implies that SLC2A3 is a dyslexia candidate that may have an indirect role in neuronal migration and/or neurite outgrowth as an energy supplier.

Looking forward

In summary, we have comprehensively reviewed the literature related to the molecular genetic findings for developmental dyslexia. To our knowledge, this article constitutes the first attempt to integrate all reported genetic findings for dyslexia into a molecular signaling network. Furthermore, we have postulated a number of additional candidate genes for dyslexia that act in this network. The theoretical molecular/cellular model we have presented mechanistically links genes involved in directed neurite outgrowth and neuronal migration, two distinct neurodevelopmental processes that use an overlapping molecular (that is genetic) machinery. Our model does not provide further insights into which of these neurodevelopmental processes would be most relevant to the etiology of dyslexia, or where in the brain these processes are localized to selectively impact on neural circuitry determining reading and spelling performance. Although we were able to place 10 of the 14 dyslexia candidate genes that were suggested by the literature in the theoretical network, it is unlikely that there would just be a single explanatory model that connects all dyslexia candidate genes and their corresponding proteins on the molecular level. Rather, several etiological cascades contributing to dyslexia are likely to exist.

That being said, we think that the model identified in this paper makes important predictions about genes and functional relationships between genes that need to be directly tested in future studies.

Therefore, we think that a number of additional genetic association and mutation studies as well as functional studies—for example neuroimaging studies and studies in animal models—will be needed to sustain some of the claims made here. In this respect, we also hope that in the next few years, results of additional, large genome-wide studies of dyslexia and reading-related phenotypes will become available in order to provide more clues for further unraveling the genetic etiology of dyslexia.

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Acknowledgements

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).

Author information

Affiliations

  1. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    • G Poelmans
    •  & J K Buitelaar
  2. Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    • D L Pauls
  3. Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    • B Franke
  4. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    • B Franke

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to B Franke.