January 10th, 2018
Association of Dyslexia with Genes – Functions of KIAA0319
The protein encoded by KIAA0319 gene is an integral membrane protein (IMP) that comprises of a small intracellular c- terminus, a single transmembrane domain, and a large extracellular domain (Gabel et al. 177). All of the splice variants of KIAA0319 are glycosylated with one form being a secretory protein (Gabel et al. 177). The core function of KIAA0319 gene product is thus to serve for signaling purposes, but the occurrence of 5 PKD domains in its extracellular domain has suggested a cell adhesion role in kidney cells (Gabel et al. 177). Currently, only one protein interactor of KIAA0319 protein – adaptor protein-2; AP-2 – has been characterized (Gabel et al. 177). AP-2 functions in the endosomal pathway (Gabel et al. 177), which is a pathway through which cells for instance internalize hydrophobic molecules that may otherwise not cross the largely lipophilic cell membrane.
Following its association with RD, studies testing for KIAA0319’s role in neuronal migration have started gaining root. One such study conducted by Paracchini et al. showed that in the presence of a Dyslexia-associated risk haplotype that has been identified on chromosome 6p22.2 – which comprises the entire TTRAP gene and portions of THEM2 and KIAA0319 – only the expression of KIAA 0319 appeared to be reduced but not those of the other two genes (Paracchini et al. 1659). Unlike TTRAP and THEM2 whose expression in the brain is ubiquitous, in situ hybridization data of expression in Paracchini et al. study indicated that KIAA0319 expression is relatively specific (1662). Such embryonic assays indicated low-intensity expression of KIAA0319 in early embryonic forms (E 13.5) “in the frontal neocortex, ganglionic eminence, mesencephalon and cerebellum”, with increasing expression being noted in later embryonic forms (E.15.5 and E18.5) (Paracchini et al. 1662). In adult mouse brain, KIAA0319 expression was noted to be intense in the “CA3 region of the hippocampus and dentate gyrus … and in the Purkinje cell layer of the adult mouse cerebellum” (Paracchini et al. 1662). Such expression patterns have also been observed in early fetal human brain (Paracchini et al. 1662).
With regard to its neuronal migration role, Paracchini et al. noted that under KIAA0319 transfection, the migration of the neurons from the VZ was significantly limited as compared to migration under the control conditions (Paracchini et al. 1664). Additionally, this impaired migration resulted into an altered morphology of the migrating neurons (Paracchini et al. 1664). Unlike in the normal status where migrating neurons’ cellular processes are parallel and closely apposed to radial glial fibers, in the neurons treated with KIAA0319-targetted shRNA, their orientation with respect to glial fibers was largely perpendicular (Paracchini et al. 1664). Since migration of neurons is thought to be guided by glial fibers (Nadarajah and Parnavelas as cited in Paracchini et al. 1664), the noted change in morphology in transfection conditions may imply that KIAA0319 has a role in facilitating “the appropriate adhesion between migrating neurons and radial glial fibers” (Paracchini et al. 1664). Such a suggestion would however require further research to prove its validity (Gabel et al. 177). Go to part 5 here.