Association of Dyslexia with Genes – Functions of DYX1C1

The functions of DYX1C1 can firstly be elucidated from its structural components. Its protein domains include “an N-terminal p23 and three C-terminal tetratricopeptide repeat (TPR) domains” (Gabel et al. 176). When over expressed in cell lines, the N-terminal p23 can interact with heat shock proteins (Hsp70 and Hsp90) and an E-3 ubiquitin ligase, CHIP; C-terminus of Hsc70-interacting protein, indicating that the gene product may be involved in the degradation of unfolded proteins (Gabel et al. 176). For instance, Massinen et al. in a study published in 2009 have reported possible involvement of DYX1C1 in oestrogen-receptor degradation, with such involvement suggested to proceed through DYX1C1 interaction with CHIP (qtd. in Gabel et al. 176).

Observations that genetic defects could be associated with neurobehavioral disorders, have however led to the evaluation of the role, if any, of candidate genes in neuronal migration. Significant progress in this respect has been in in vivo studies that use RNA interference (RNAi) methods to assess the effect of such interference on neuronal migration. Wang et al. for instance explored “the developmental function of DYX1C1 in embryonic neocortex of the rat by in utero RNAi” (515). The study first examination was designed to assess whether DYX1C1 (DYX1C1 gene product) is involved in neuronal migration using short hairpin RNA (shRNA) vectors that were capable of limiting the expression of “DYX1C1 protein by 30-70% in cos7 cells” (Wang et al. 518). Measurement of the effect of such interference on in vivo migration of neurons was assessed via the in utero electroporation and RNAi method described by Bai et al. in their 2003 study (Wang et al. 518). Such assessment involves the quantification – by measurement of the “shortest distance between [ventricular zone; VZ] surface and soma of each cell” – of the distance over which cells that have been “initially transfected and labeled at the VZ surface”, migrate from the VZ surface (Wang et al. 518).   The study’s findings indicated that RNAi resulting from the transfection of DYX1C1 with shRNA vectors resulted into decreased migration from VZ surface as compared to two controls; one with cells transfected with beta-3-tubulin-targeted shRNA control plasmids that do not impair migration, and the other with shRNA control plasmids that have a three-base mismatch (Wang et al. 521). Such impaired migration in the cells transfected with the shRNAs that impended expression of DYX1C1, was restored to comparable levels with the controls, after transfection of pCA-Dyx-eGFP, which enhanced the expression of DYX1C1 (Wang et al. 521). Other explanations that could be made for the impaired migration, other than the curtailed expression of DYX1C1, such as the reduced migration being a result of cell-cycle disruption were discounted through further assays (Wang et al. 521). From such observations, Wang et al. thus concluded one of the functions of DYX1C1 to be ensuring effective neuronal migration takes place (522).

A second concern of the Wang et al. study was to identify the stage of neuronal migration where the DYX1C1 plays a critical role. This was possible since morphological changes that characterize the migration of neurons in the neocortex correspond to different stages in the migration process. From their bipolar progenitor-form, and associated precursor-forms in the VZ, migrating neurons “become multipolar and branched as they exit the VZ and enter the lower [intermediate zone; IZ]” (Wang et al. 519). The neurons then revert to the bipolar morphology within the IZ “as they migrate toward and into the [cortical plate; CP]” (Wang et al. 519). Following reports from other studies (e.g. Nagano et al. qtd. in Wang et al. 519) indicating the stage where the neurons transition into and out of the multipolar stage is vulnerable to disruptions, Wang et al. thus examined the function of DYX1C1 as neurons transition out of the multipolar stage (Wang et al. 519). This was by comparing “the percentages of transfected neurons that were in the bipolar and multipolar stages within the SVZ and IZ, 1, 2, and 4, days following transfection” (Wang et al. 519). From the comparison, the transitioning into the multipolar stage seemed unaffected since the number of cells in that stage was comparable for both test and controls (Wang et al. 519). However, for the transitioning out from the multipolar morphology into the bipolar morphology, whereas most control cells had reverted into bipolar morphology, most cells treated to curtail the expression of DYX1C1 remained in their multipolar morphological forms (Wang et al. 519). From this observation, Wang et al. (522) concluded that DYX1C1 role is at such multipolar transition out stage, but not in the multipolar transition in stage.

Thirdly, Wang et al.’s study (515-512) provided insight into the importance of C-terminal TRP domains of DYX1C1 in ensuring its functional integrity in respect to neuronal migration. Through their experiment, where they used truncation mutants to rescue the DYX1C1 RNAi treated cells, results showed that TRP domains of DYX1C1 are critical in ensuring effective migration process (Wang et al. 519). In rescued mutants that missed the TRP domain, the migration remained curtailed, while in those where the expression of TRP domains was restored, normal migration resumed (Wang et al. 519). Further, deletion of a 3-amino acid residue at the last TPR, which is attributed to a single nucleotide polymorphism (SNP) that was initially associated with RD (Gabel et al. 177), was not shown to affect the role of DYX1C1 in the Wang et al. study (519,521).

Reinforcing the hypothesis that DYX1C1 functions in neuronal migration, has been a study by Rosen et al that examined the effect of DYX1C1 targeted RNAi in the brains of adult rats (2562). In this study, the authors hypothesized that abnormalities resulting from a knockdown of DYX1C1 would resemble those observed in postmortem assays of dyslexic brains (2562). The study found that in a period of four days following transfection of DYX1C1, the migration of neurons into the CP was almost completely blocked (Rosen et al. 2567). Further such blockade was alleviated by concurrent overexpression of Dyx1c1 thus tracing the noted effect to the knockdown of Dyx1c1 (Rosen et al. 2567). Despite indications that most neurons recovered their migration potential and attained positions of migration similar to those of controls in adults, laminar displacement of shRNA transfected neurons in the cortex persisted even in adult rodents (Rosen et al. 2564-2566). Additionally, distinct malformations such as heterotopias in the white matter, hippocampal malformations and ectopias in the cerebral cortex were noted in different animals whose brains were subjected to Dyx1c1 knockdown (Rosen et al. 2565-2567). Such malformations are correlated with observations noted in postmortem assays of dyslexics’ brains (Rosen et al. 2564). Through these experiments the role DYX1C1 in ensuring effective neuronal migration is implied, with mutations that result into curtailed expression DYX1C1 probably resulting into neurobehavioral disorders such as dyslexia

Implicated Genes at Locus DYX2 – KIAA0319 and DCDC2

DYX2, the most replicated of DYX loci, has been associated with various RD phenotypes in different studies (Gabel et al. 175). Particularly, studies have identified two peaks within DYX2 that are associated with RD, which include the genes KIAA0319 and DCDC2 (Gabel et al. 175). One study published in 2002, for instance reported the association of RD with 5′ non-coding region of KIAA0319 (Kaplan et al. cited in Gabel et al. 175). Subsequent studies (e.g. Francks et al. in 2004 and Cope et al. in 2005) identified association to exist in a 77 kb region that comprises the first four exons of KIAA0319 (qtd. in Gabel et al. 175). Further assays identified such risk to reduced expression of KIAA0319 after observation that other genes in that locus did not confer such a risk (Gabel et al. 175).  A more recent study cited by Gabel et al. (175), has attributed the risk to curtailed promoter activity and impaired binding to the transcriptional silencer, OCT-1.

A second gene implicated to exhibit vulnerability for dyslexia in the DYX2 locus is DCDC2, which is located 500kb from KIAA0319 gene (Gabel et al. 175). In one study that used a sample of 153 dyslexic families, DCDC2 association with RD was attributed to a compound short tandem repeat (STR) occurring in intron 2 (Meng et al. 17503). In an independent study conducted in Germany and published in 2006, Schumacher et al. also indicated such DCDC2’s association with RD; this association has further been replicated in an Italian cohort study carried out by Meng et al. that has attributed the risk to a reduced enhancer activity (qtd. in Gabel et al. 175). Go to part 4 here.

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