Progress towards a cellular neurobiology of reading disability

Abstract

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 wellestablished 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.

A theoretical molecular network for dyslexia: integrating available genetic findings

“…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. 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.…”

“…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.…”

“…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 signalregulated kinase 1 (ERK1) and 2 (ERK2) proteins.…”

“…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.…”

Pleiotropic functions of EAPII/TTRAP/TDP2

“…79 It was hypothesized that impaired neuronal migration is a cellular neurobiological antecedent to RD. 80 Genetic linkage studies have identified Chromosome 6p23-21.3, where EAPII is located, as one of the potential loci related to RD. 7,[81][82][83][84][85][86][87] Within this locus, a 77-kilobase region spans the EAPII gene, portions of KIAA0319 and the upstream region of THEM2.…”