Various cognitive domains support literacy acquisition Thus

Various cognitive domains support literacy acquisition. Thus, heterogeneous cognitive fingerprints of dyslexia phenotypes exist (Heim and Grande, 2012; Ramus and Ahissar, 2012) and multiple subtypes of dyslexia have been suggested (Bosse et al., 2007), but a bona fide theory of the underlying mechanisms has not been established yet. A widely accepted rationale bases dyslexia on an impairment of phonological representations (Snowling, 2001). Others advocate auditory processing deficits such as an impaired oscillatory phase locking for low frequency temporal coding in auditory purchase leptomycin b (Goswami, 2011), or a decreased sensitivity to rapidly changing phonological features (Benasich et al., 2002; Tallal, 1980). Auditory processing deficits might cause an impoverished distinction between speech sounds (Vandermosten et al., 2010), a deficient access to otherwise intact phonetic representations (Boets et al., 2013), or a deficient match between memory representations and auditory sensations (Díaz et al., 2012; Jaffe-Dax et al., 2015). Alternatively or additionally, visual attention, visual-magnocellular processing, or visual-auditory integration compose further cognitive problems (Heim et al., 2010; Stein and Walsh, 1997; Valdois et al., 2014; Widmann et al., 2012). Dyslexia is moderately to highly heritable (Schumacher et al., 2007) with a multifactorial etiology (Fisher and DeFries, 2002) and a complex underlying genetic architecture. Evidence exists for multiple genes to contribute to the phenotype, with considerable genetic heterogeneity across individuals (Carrion-Castillo et al., 2013). Dyslexia is linked to several risk loci including nine so-called DYX-regions (DYX1-DYX9) (Carrion-Castillo et al., 2013; Giraud and Ramus, 2013; Peterson and Pennington, 2012; Poelmans et al., 2011), but a consistent genome-wide association is still missing. However, DYX2 on chromosome 6 is the best replicated susceptibility locus (Gabel et al., 2010), with DCDC2 (Lind et al., 2010; Ludwig et al., 2008; Meng et al., 2005; Newbury et al., 2011; Scerri et al., 2011; Schumacher et al., 2006; Wilcke et al., 2009) as well as KIAA0319 (Cope et al., 2005; Francks et al., 2004; Harold et al., 2006; Kaplan et al., 2002; Luciano et al., 2007; Meng et al., 2005; Paracchini et al., 2008; Scerri et al., 2011) as strongest candidate genes of this locus. Numerous studies evaluate the genetic origin of dyslexia, excellently compiled in recent reviews (Carrion-Castillo et al., 2013; Giraud and Ramus, 2013). Despite considerable progress, complex gene-brain relations of KIAA0319 and DCDC2 are far from comprehensive, because studies elucidating the genes’ impact on cell anatomy and systems physiology are scarce. Animal experiments associate the functional role of both genes with neuronal migration (Burbridge et al., 2008; Meng et al., 2005; Paracchini et al., 2006; Peschansky et al., 2010) and, thus, a role in the formation of the neuronal cell assemblies during brain development. Furthermore, both genes are expressed in mature neurons after migration and contribute to protein binding. More specifically, KIAA0319 encodes an integral transmembrane protein (Velayos-Baeza et al., 2010), and is a component in the early endosome, its membrane and the plasma membrane, possibly supporting a broader spectrum of signaling functions. In addition to neuronal migration, KIAA0319 is associated with a negative regulation of dendrite development. It regulates processes that stop, prevent or reduce the frequency, rate or extent of dendrite development (http://www.ncbi.nlm.nih.gov.eleen.top/gene/9856; Gene ID: 9856, updated on 6-Mar-2016). Animal studies indicated that in utero RNA interference (RNAi) targeting Kiaa0319 in male Wistar rats affected acoustic discrimination abilities of complex stimuli, which was associated with formation of heterotopias in white matter (Szalkowski et al., 2013). Electrophysiologically, a downregulation of Kiaa0319 expression was followed by a decreased response consistency to sound stimuli as measured from neurons in the primary auditory cortex, resulting in a reduced neuronal discrimination ability (Centanni et al., 2014a,b).