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    • At the cellular level DCDC is involved in

    2018-10-29

    At the cellular level DCDC2 is involved in processes such as cellular defense response, dendrite morphogenesis, intracellular signal transduction, regulation of smoothened signaling pathway, regulation of Wnt signaling pathway, and regulation of cilium assembly. At the systems level, DCDC2 is correlated with visual learning and sensory perception of sound. DCDC2 is a component of axoneme, cytoplasm, cytoskeleton, kinocilium, nucleus and primary cilium. The doublecortin domain, to which DCDC2 belongs, has been shown to bind tubulin and enhance microtubule polymerization. Its function may affect the signaling of primary c-kit inhibitor (http://www.ncbi.nlm.nih.gov.eleen.top/gene/51473; Gene ID: 51473, updated on 6-Mar-2016). DCDC2 has been reported to be a deafness gene in a Tunisian family motivated by the considerations that hair cell kinocilia and cell primary cilia length regulation is likely influenced by DCDC2’s role in microtubule formation and stabilization (Szalkowski et al., 2012). Dcdc2 knockout mice showed a deficit in rapid auditory processing (Truong et al., 2014), which is consistent with the observation of degraded neural spike timing and, thus, difficulties in the encoding of rapid sequential sensory input as measured in the somatosensory cortex in the same mutants (Che et al., 2014). Taken together, auditory processing deficits have been linked to gene homologues for both genes (Centanni et al., 2014a,b; Szalkowski et al., 2012; Truong et al., 2014). The physiological consequence of altered functions of KIAA0319 and DCDC2 is linked to imprecise neuronal temporal coding. It is plausible to assume that an imprecise encoding of acoustic input leads to processing deficits of ascending speech signals challenging the formation of robust phoneme representations in long-term memory. Thus, a temporal processing deficit might prevent the uncomplicated acquisition and consolidation of literacy skills as suggested by dominating theories (Goswami, 2011; Tallal, 2012). A huge body of brain-behavior association studies report altered structural and functional correlates pointing to irregular auditory and phonological processes in dyslexia (Banai et al., 2005; Díaz et al., 2012; Hämäläinen et al., 2013; Hornickel and Kraus, 2013; Kujala et al., 2006; Paulesu et al., 2014; Schulte-Körne and Bruder, 2010). Several brain-gene studies considered KIAA0319 and DCDC2 in the context of literacy. Late electrophysiological responses to speech sounds (300–700ms) are affected in rare variants in a region between KIAA0319 and DCDC2 (Czamara et al., 2010). A KIAA0319/TTRAP/THEM2 locus was associated with a reduced left-hemispheric functional asymmetry of posterior superior temporal sulcus during reading (Pinel et al., 2012). The KIAA0319 single nucleotide polymorphism rs2143340 was related to activation in the bilateral supramarginal gyri during a word rhyming task (Cope et al., 2012). In the same study, alleles of a DCDC2 complex tandem repeat were related to activation in the right lateral occipital temporal gyrus and the left supramarginal gyrus. These gene-related abnormal functional activations in the parietal lobes are consistent with the DCDC2-related reduced white matter volume, and a degraded cortical thickness in the same region (Darki et al., 2014). The impact of dyslexia risk genes on early auditory processing is currently unknown. Interestingly, the sensation related processing of speech sounds has been found to be noisy at a very early stage in the auditory pathway of poor readers. Speech evoked brainstem responses (cABRs) were unstable and indistinctive in poor readers and in children with poor phonological skills (Banai et al., 2005; Chandrasekaran et al., 2009; Hornickel et al., 2009; Hornickel and Kraus, 2013; Strait et al., 2011; White-Schwoch and Kraus, 2013). Particularly striking is the sensitivity of cABRs in the phase of the formant transition of a given stimulus (Hornickel and Kraus, 2013). Formant transitions are fast changes of frequency bands that constitute important phonetic features because a correct encoding of formant transitions enables us to distinguish between stop consonants. Ultimately, we investigated how the two prominent dyslexia susceptible genes DCDC2 and KIAA0319 relate to the stability of speech-evoked brainstem responses in the phase of the formant transition of the syllable [da], which has been reported to be an electrophysiological marker of dyslexia in the early auditory pathway (Hornickel and Kraus, 2013). Here, we provide the first evidence that the dyslexia-associated gene KIAA0319 affects response consistency in the auditory brainstem and, thus, impairs phoneme encoding at a very early stage in the auditory pathway.