January 10th, 2018
Association of Dyslexia with Genes – Functions of DCDC2
One of the distinguishing features of the eleven-member family of proteins to which DCDC2 gene product belongs, is the presence of doublecortin domains; dcx (Gabel et al. 177). One of the members of this class, DCX, was the first to be characterized, its mutations being noted to cause “double cortex syndrome in females and lissencephaly in males” (Gabel et al. 177). In all members of this family of proteins, the dcx domain functions to bind and stabilize microtubules – the cytoplasmic tubular structures that are components of the cytoskeleton – with such activity being regulated by phosphorylation (Gabel et al. 177). Interaction between two of the members of the dcx family – Dcx and Dclk – in animal studies has been observed to facilitate “growth of axons across the corpus callosum and in neuronal migration in the cerebral cortex” (Gabel et al. 177). Dcdc2 has been found to exhibit same functional features as these two members in comparative studies of proteins’ biochemical and cellular functions, such a similarity suggested to partially arise from its structural resemblance with Dcx proteins (Gabel et al. 177).
Arising from such structural similarity, studies have tried to assess a potential role of DCDC2 in neuronal migration. One such study by Meng et al. highlighted such a role of DCDC2 in their quest to identify the DYX2 gene locus and its associated variants that harbor vulnerability for RD (17053). Following in utero RNAi assay, migration of cells that had been treated with plasmid vectors encoding DCDC2-targeted shRNA, was significantly curtailed in comparison with cells transfected with control plasmids (Meng et al. 17056). A more recent study cited by Gabel et al. (177) has reinforced the suggested neuronal migration role for DCDC2. In this later study conducted by Burbridge et al. and published in 2008, Dcdc2 knockdown was shown to result into similar but not identical disruptions as those noted in Dyx1c1 knockdown (as cited in Gabel et al. 177). Such knockdown for instance resulted in scattered heterotopia within the white matter, with a resemblance to periventricular nodular heterotopia (PNH) and an over migration of neurons to ectopic regions in the neocortex without resulting to ectopia (Gabel et al. 177). Such over migration is not resolved even with rescue experiments that revert the PNH malformations, suggesting that the over migration may be a secondary effect of the delayed migration rather than a direct effect of DCDC2 knockdown (Gabel et al. 177).
Other Genes Exhibiting Susceptibility to Dyslexia
Apart from the three genes whose association has been replicated in large populations, other candidate genes have been observed in different studies but not in large populations. One such gene is ROBO1 where “disruptions between exon 1 and 2 … on 3p” were observed in a Finnish RD individual (Gabel et al. 175). ROBO1 is located in DYX5 locus on the genome and further assays have identified the disruptions to a SNP haplotype that spans the gene (Gabel et al. 177). ROBO1 plays critical roles in axonal targeting and cell migration (Galaburda et al. 1214) hence its association with RD susceptibility presents a basis for studies linking RD to development of axonal connections (Gabel et al. 175).
From these reviews, it appears that genetic susceptibility to RD may be a result of disruptions in neuronal migration. However, the majority of genetic risk to RD has not been identified to the genes whose curtailed expression has been associated with impaired neuronal migration (Gabel et al. 177). Animal models that portray abnormalities observed in postmortem assays of dyslexics’ brains and associated with impairment of neuronal migration may however present further basis for identifying genetic links to neurobehavioral disorders noted in such animals. Go to part 6 here.