Identification of host essential factors for recombinant AAV transduction of the polarized human airway epithelium.

IMPORTANCE: The essential steps of successful gene delivery by recombinant adeno-associated viruses (rAAVs) include vector internalization, intracellular trafficking, nuclear import, uncoating, double-stranded (ds)DNA conversion, and transgene expression. rAAV2.5T has a chimeric capsid of AAV2 VP1u and AAV5 VP2 and VP3 with the mutation A581T. Our investigation revealed that KIAA0319L, the multiple AAV serotype receptor, is not essential for vector internalization but remains critical for efficient vector transduction to human airway epithelia. Additionally, we identified that a novel gene WDR63, whose cellular function is not well understood, plays an important role in vector transduction of human airway epithelia but not vector internalization and nuclear entry. Our study also discovered the substantial transduction potential of rAAV2.5T in basal stem cells of human airway epithelia, underscoring its utility in gene editing of human airways. Thus, the knowledge derived from this study holds promise for the advancement of gene therapy in the treatment of pulmonary genetic diseases.

Genetic determinants of individual variation in the superior temporal sulcus of chimpanzees (Pan troglodytes).

The superior temporal sulcus (STS) is a conserved fold that divides the middle and superior temporal gyri. In humans, there is considerable variation in the shape, folding pattern, lateralization, and depth of the STS that have been reported to be associated with social cognition and linguistic functions. We examined the role that genetic factors play on individual variation in STS morphology in chimpanzees. The surface area and depth of the STS were quantified in sample of 292 captive chimpanzees comprised of two genetically isolated population of individuals. The chimpanzees had been previously genotyped for AVPR1A and KIAA0319, two genes that play a role in social cognition and communication in humans. Single nucleotide polymorphisms in the KIAA0319 and AVPR1A genes were associated with average depth as well as asymmetries in the STS. By contrast, we found no significant effects of these KIA0319 and AVPR1A polymorphism on surface area and depth measures for the central sulcus. The overall findings indicate that genetic factors account for a small to moderate amount of variation in STS morphology in chimpanzees. These findings are discussed in the context of the role of the STS in social cognition and language in humans and their potential evolutionary origins.

Cumulative genetic score of KIAA0319 affects reading ability in Chinese children: moderation by parental education and mediation by rapid automatized naming.

KIAA0319, a well-studied candidate gene, has been shown to be associated with reading ability and developmental dyslexia. In the present study, we investigated whether KIAA0319 affects reading ability by interacting with the parental education level and whether rapid automatized naming (RAN), phonological awareness and morphological awareness mediate the relationship between KIAA0319 and reading ability. A total of 2284 Chinese children from primary school grades 3 and 6 participated in this study. Chinese character reading accuracy and word reading fluency were used as measures of reading abilities. The cumulative genetic risk score (CGS) of 13 SNPs in KIAA0319 was calculated. Results revealed interaction effect between CGS of KIAA0319 and parental education level on reading fluency. The interaction effect suggested that individuals with a low CGS of KIAA0319 were better at reading fluency in a positive environment (higher parental educational level) than individuals with a high CGS. Moreover, the interaction effect coincided with the differential susceptibility model. The results of the multiple mediator model revealed that RAN mediates the impact of the genetic cumulative effect of KIAA0319 on reading abilities. These findings provide evidence that KIAA0319 is a risk vulnerability gene that interacts with environmental factor to impact reading abilities and demonstrate the reliability of RAN as an endophenotype between genes and reading associations.

Toward Robust Functional Neuroimaging Genetics of Cognition.

A commonly held assumption in cognitive neuroscience is that, because measures of human brain function are closer to underlying biology than distal indices of behavior/cognition, they hold more promise for uncovering genetic pathways. Supporting this view is an influential fMRI-based study of sentence reading/listening by Pinel et al. (2012), who reported that common DNA variants in specific candidate genes were associated with altered neural activation in language-related regions of healthy individuals that carried them. In particular, different single-nucleotide polymorphisms (SNPs) of FOXP2 correlated with variation in task-based activation in left inferior frontal and precentral gyri, whereas a SNP at the KIAA0319/TTRAP/THEM2 locus was associated with variable functional asymmetry of the superior temporal sulcus. Here, we directly test each claim using a closely matched neuroimaging genetics approach in independent cohorts comprising 427 participants, four times larger than the original study of 94 participants. Despite demonstrating power to detect associations with substantially smaller effect sizes than those of the original report, we do not replicate any of the reported associations. Moreover, formal Bayesian analyses reveal substantial to strong evidence in support of the null hypothesis (no effect). We highlight key aspects of the original investigation, common to functional neuroimaging genetics studies, which could have yielded elevated false-positive rates. Genetic accounts of individual differences in cognitive functional neuroimaging are likely to be as complex as behavioral/cognitive tests, involving many common genetic variants, each of tiny effect. Reliable identification of true biological signals requires large sample sizes, power calculations, and validation in independent cohorts with equivalent paradigms.SIGNIFICANCE STATEMENT A pervasive idea in neuroscience is that neuroimaging-based measures of brain function, being closer to underlying neurobiology, are more amenable for uncovering links to genetics. This is a core assumption of prominent studies that associate common DNA variants with altered activations in task-based fMRI, despite using samples (10-100 people) that lack power for detecting the tiny effect sizes typical of genetically complex traits. Here, we test central findings from one of the most influential prior studies. Using matching paradigms and substantially larger samples, coupled to power calculations and formal Bayesian statistics, our data strongly refute the original findings. We demonstrate that neuroimaging genetics with task-based fMRI should be subject to the same rigorous standards as studies of other complex traits.

The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling.

KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 participates in functions unrelated to neuronal migration. Supporting this hypothesis, overexpression of KIAA0319 repressed axon growth in hippocampal and dorsal root ganglia neurons; the intracellular domain of KIAA0319 was sufficient to elicit this effect. A similar inhibitory effect was observed in vivo as axon regeneration was impaired after transduction of sensory neurons with KIAA0319. Conversely, the deletion of Kiaa0319 in neurons increased neurite outgrowth in vitro and improved axon regeneration in vivo. At the mechanistic level, KIAA0319 engaged the JAK2-SH2B1 pathway to activate Smad2, which played a central role in KIAA0319-mediated repression of axon growth. In summary, we establish KIAA0319 as a novel player in axon growth and regeneration with the ability to repress the intrinsic growth potential of axons. This study describes a novel regulatory mechanism operating during peripheral nervous system and central nervous system axon growth, and offers novel targets for the development of effective therapies to promote axon regeneration.

Association study of developmental dyslexia candidate genes DCDC2 and KIAA0319 in Chinese population.

Developmental dyslexia (DD) is characterized by difficulties in reading and spelling independent of intelligence, educational backgrounds and neurological injuries. Increasing evidences supported DD as a complex genetic disorder and identified four DD candidate genes namely DYX1C1, DCDC2, KIAA0319 and ROBO1. As such, DCDC2 and KIAA0319 are located in DYX2, one of the most studied DD susceptibility loci. However, association of these two genes with DD was inconclusive across different populations. Given the linguistic and genetic differences between Chinese and other populations, it is worthwhile to investigate association of DCDC2 and KIAA0319 with Chinese dyslexic children. Here, we selected 60 tag SNPs covering DCDC2 and KIAA0319 followed by high density genotyping in a large unrelated Chinese cohort with 502 dyslexic cases and 522 healthy controls. Several SNPs (Pmin = 0.0192) of DCDC2 and KIAA0319 as well as a four-maker haplotype (Padjusted = 0.0289, Odds Ratio (OR) = 1.3400) of KIAA0319 showed nominal association with DD. However, none of these results survived Bonferroni correction for multiple comparisons. Thus, the association of DCDC2 and KIAA0319 with DD in Chinese population should be further validated and their contribution to DD etiology and pathology should be interpreted with caution.

Engineering a highly durable adeno-associated virus receptor for analytical applications.

Adeno-associated virus (AAV) is a major viral vector used in gene therapy. There are multiple AAV serotypes, and many engineered AAV serotypes are developed to alter their tissue tropisms with capsid modification. The universal AAV receptor (AAVR) is an essential receptor for multiple AAV serotypes. Since most AAV serotypes used in gene therapy infect cells via interaction with AAVR, the quantification of the vector-binding ability of AAV to AAVR could be an important quality check for therapeutic AAV vectors. To enable a steady evaluation of the AAV-AAVR interaction, we created an engineered AAVR through mutagenesis. Engineered AAVR showed high durability against acid while retaining its AAV-binding activity. An affinity chromatography column with the engineered AAVR was also developed. This column enabled repeated binding and acid dissociation measurements of AAVR with various AAV serotypes. Our data showed that the binding affinities of AAV2 to AAVR were diverse among serotypes, providing insight into the relationship with the infection efficiency of AAV vectors. Thus, this affinity column can be used in process development for quality checks, quantitating capsid titers, and affinity purification of AAV vectors. Furthermore, this column may serve as a useful tool in novel AAV vector capsid engineering.

Dyslexia associated gene KIAA0319 regulates cell cycle during human neuroepithelial cell development.

Dyslexia, also known as reading disability, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of dyslexia is between 5 and 17%, and the heritability ranges from 44 to 75%. Genetic linkage analysis and association studies have identified several genes and regulatory elements linked to dyslexia and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. The association of KIAA0319 with reading performance has been replicated in independent studies and different languages. Rodent models suggest that kiaa0319 is involved in neuronal migration, but its role throughout the cortical development is largely unknown. In order to define the function of KIAA0319 in human cortical development, we applied the neural developmental model of a human embryonic stem cell. We knocked down KIAA0319 expression in hESCs and performed the cortical neuroectodermal differentiation. We found that neuroepithelial cell differentiation is one of the first stages of hESC differentiation that are affected by KIAA0319 knocked down could affect radial migration and thus differentiation into diverse neural populations at the cortical layers.

Rapid auditory processing and medial geniculate nucleus anomalies in Kiaa0319 knockout mice.

Developmental dyslexia is a common neurodevelopmental disorder characterized by difficulties in reading and writing. Although underlying biological and genetic mechanisms remain unclear, anomalies in phonological processing and auditory processing have been associated with dyslexia. Several candidate risk genes have also been identified, with KIAA0319 as a main candidate. Animal models targeting the rodent homolog (Kiaa0319) have been used to explore putative behavioral and anatomic anomalies, with mixed results. For example after downregulation of Kiaa0319 expression in rats via shRNA, significant adult rapid auditory processing impairments were reported, along with cortical anomalies reflecting atypical neuronal migration. Conversely, Kiaa0319 knockout (KO) mice were reported to have typical adult auditory processing, and no visible cortical anomalies. To address these inconsistencies, we tested Kiaa0319 KO mice on auditory processing tasks similar to those used previously in rat shRNA knockdown studies. Subsequent neuroanatomic analyses on these same mice targeted medial geniculate nucleus (MGN), a receptive communication-related brain structure. Results confirm that Kiaa0319 KO mice exhibit significant auditory processing impairments specific to rapid/brief stimuli, and also show significant volumetric reductions and a shift toward fewer large and smaller neurons in the MGN. The latter finding is consistent with post mortem MGN data from human dyslexic brains. Combined evidence supports a role for KIAA0319 in the development of auditory CNS pathways subserving rapid auditory processing functions critical to the development of speech processing, language, and ultimately reading. Results affirm KIAA0319 variation as a possible risk factor for dyslexia specifically via anomalies in central acoustic processing pathways.

Dyslexia and Attention Deficit Hyperactivity Disorder Associated to a De Novo 1p34.3 Microdeletion.

The authors report on a boy with dyslexia and attention deficit hyperactivity disorder. A protocol of standardized tests assessed the neuroadaptive profile, allowing deep neuropsychiatric phenotyping. In addition to the diagnosis of dyslexia and attention deficit hyperactivity disorder, such methodology led to endeavor cognitive, adaptive, and academic skills. Chromosomal microarray analysis detected a 452.4 Kb de novo heterozygous microdeletion in chromosomal region 1p34.3, including seven OMIM genes. The authors took a thorough evaluation of the association to the phenotype of the deleted genes. Further reports could strengthen such association.

Gray Matter Variation in the Posterior Superior Temporal Gyrus Is Associated with Polymorphisms in the KIAA0319 Gene in Chimpanzees (Pan troglodytes).

Determining the impact that the KIAA0319 gene has on primate brain morphology can provide insight into the evolution of human cognition and language systems. Here, we tested whether polymorphisms in KIAA0319 in chimpanzees account for gray matter volumetric variation in brain regions implicated in language and communication (particularly within the posterior superior temporal gyrus and inferior frontal gyrus). First, we identified the nature and frequencies of single nucleotide variants (SNVs) in KIAA0319 in a sample of unrelated chimpanzees (Pan troglodytes spp.). Next, we genotyped a subset of SNVs (those important for gene regulation or likely to alter protein structure/function) in a sample of chimpanzees for which in vivo T1-structural magnetic resonance imaging scans had been obtained. We then used source-based morphometry (SBM) to test for whole-brain gray matter covariation differences between chimpanzees with different KIAA0319 alleles. Finally, using histologic sections of 15 postmortem chimpanzee brains, we analyzed microstructural variation related to KIAA0319 polymorphisms in the posterior superior temporal cortex. We found that the SNVs were associated with variation in gray matter within several brain regions, including the posterior superior temporal gyrus (a region associated with language comprehension and production in humans). The microstructure analysis further revealed hemispheric differences in neuropil fraction, indicating that KIAA0319 expression may be involved in regulation of processes related to the formation and maintenance of synapses, dendrites, or axons within regions associated with communication.

microRNA-592 blockade inhibits oxidative stress injury in Alzheimer's disease astrocytes via the KIAA0319-mediated Keap1/Nrf2/ARE signaling pathway.

MicroRNA-592 (miR-592) has been reported to play a significant role in mediating neuronal activity, but its possible link with Alzheimer's disease (AD) remains unclear. We aimed to explore the mechanism of miR-592 in oxidative stress (OS) injury of astrocytes (ASTs) from AD rat models induced by D-galactose or Aß25-35 injection. Bioinformatics website and dual-luciferase reporter gene assay clarified the binding affinity between miR-592 and KIAA0319. KIAA0319 was identified as a target gene of miR-592. The mechanism of miR-592, KIAA0319 and the Keap1/Nrf2/ARE signaling pathway in AD was examined after transducing miR-592 mimic, miR-592 inhibitor and siRNA-KIAA0319 into ASTs to query cell viability, OS injury and reactive oxygen species (ROS). The rat models of AD Exhibited highly expressed miR-592 and poorly expressed KIAA0319. Furthermore, inhibition of miR-592 diminished C-Keap1 expression and enhanced N-Nrf2 and NQO1 expression, thus promoting cell viability and reducing OS injury of ASTs. Taken together, these findings suggested that the downregulation of miR-592 inhibited OS injury of ASTs in rat models of AD by up-regulating KIAA0319 through the activation of the Keap1/Nrf2/ARE signaling pathway.

Pooled Screens Identify GPR108 and TM9SF2 as Host Cell Factors Critical for AAV Transduction.

Adeno-associated virus (AAV) has been used extensively as a vector for gene therapy. Despite its widespread use, the mechanisms by which AAV enters the cell and is trafficked to the nucleus are poorly understood. In this study, we performed two pooled, genome-wide screens to identify positive and negative factors modulating AAV2 transduction. Genome-wide libraries directed against all human genes with four designs per gene or eight designs per gene were transduced into U-2 OS cells. These pools were transduced with AAV2 encoding EGFP and sorted based on the intensity of EGFP expression. Analysis of enriched and depleted barcodes in the sorted samples identified several genes that putatively decreased AAV2 transduction. A subset of screen hits was validated in flow cytometry and imaging studies. In addition to KIAA0319L (AAVR), we confirmed the role of two genes, GPR108 and TM9SF2, in mediating viral transduction in eight different AAV serotypes. Interestingly, GPR108 displayed serotype selectivity and was not required for AAV5 transduction. Follow-up studies suggested that GPR108 localized primarily to the Golgi, where it may interact with AAV and play a critical role in mediating virus escape or trafficking. Cumulatively, these results expand our understanding of the process of AAV transduction in different cell types and serotypes.

Structural and cellular biology of adeno-associated virus attachment and entry.

Adeno-associated virus (AAV) is a nonenveloped, ssDNA virus in the parvovirus family, which has become one of the leading candidate vectors for human gene therapy. AAV has been studied extensively to identify host cellular factors involved in infection, as well as to identify capsid variants that confer clinically favorable transduction profiles ex vivo and in vivo. Recent advances in technology have allowed for direct genetic approaches to be used to more comprehensively characterize host factors required for AAV infection and allowed for identification of a critical multi-serotype receptor, adeno-associated virus receptor (AAVR). In this chapter, we will discuss the interactions of AAV with its glycan and proteinaceous receptors and describe the host and viral components involved in AAV entry, which requires cellular attachment, endocytosis, trafficking to the trans-Golgi network and nuclear import. AAV serves as a paradigm for entry of nonenveloped viruses. Furthermore, we will discuss the potential of utilizing our increased understanding of virus-host interactions during AAV entry to develop better AAV-based therapeutics, with a focus on host factors and capsid interactions involved in in vivo tropism.

Retrograde gene transfer into neural pathways mediated by adeno-associated virus (AAV)-AAV receptor interaction.

BACKGROUND: Viral vector systems delivering transgenes in the retrograde direction through axons to neural cell bodies are powerful experimental tools for the functional analysis of specific neural pathways. Generally, the efficiency of viral vector-mediated retrograde gene transfer depends on the expression of requisite viral receptors in neural pathways projecting to the viral vector-injected regions. This is known as viral tropism and can limit the utility of retrograde viral vectors. The adeno-associated virus (AAV) vector has become an increasingly popular platform for gene delivery to neural cells in vivo, and it is therefore meaningful to develop a new type of retrograde gene transfer approach based on a tropism-free AAV vector system. NEW METHOD: The wild-type or mutant receptor gene of AAV was expressed to mitigate AAV tropism. RESULTS: Efficient AAV vector-mediated retrograde gene transfer was observed in diverse neural pathways by expression of the AAV receptor (AAVR) gene. Moreover, the expression of a minimal mutant of AAVR (miniAAVR), which maintains binding potential to AAV, demonstrated efficient retrograde gene expression comparable to that of AAVR. COMPARISON WITH EXISTING METHODS: The utility of existing AAV vector-mediated retrograde gene delivery methods is sometimes limited by tropism. Our newly developed AAV-AAVR and AAV-miniAAVR interaction approaches enabled efficient retrograde gene transfer into various neural pathways by mitigating tropism. CONCLUSIONS: AAV-AAVR and AAV-miniAAVR interaction approaches enabled us to induce efficient retrograde gene expression in targeted neural pathways and provide a powerful tool for analyzing specific neural pathways.

The Influence of Developmental Dyslexia-associated Gene KIAA0319 on Brain Development——From Animals to Humans / 生物化学与生物物理进展

Developmental dyslexia (DD) is a prevalent learning disorder, and the KIAA0319 gene is a DD-associated gene, potentially affecting reading ability by influencing brain development. This review provides an overview of the impact of KIAA0319 gene on brain development in fish, non-primate mammals, primate mammals, and humans. In studies involving fish, the kiaa0319 gene was found to be expressed in the brain, eyes and ears of zebrafish. In mammalian studies, abnormal Kiaa0319 gene expression affected neuronal migration direction and final position, as well as dendritic morphology during embryonic development in rats, leading to abnormal white and gray matter development. Knocking down the Kiaa0319 gene impaired the primary auditory cortex in rats, resulting in phoneme processing impairment similar to DD. In mice, Kiaa0319 overexpression affected the neuronal migration process, causing delayed radial migration of neurons to the cortical plate. Knockout of the Kiaa0319 gene led to abnormal development of the gray matter in mice, resulting in reduced volume of the medial geniculate nucleus and then impacting auditory processing. In primate studies, research on marmosets found that KIAA0319 gene is expressed in the visual, auditory, and motor pathways, while studies on chimpanzees revealed that KIAA0319 gene abnormalities primarily affected the gray matter volume and microstructure of the posterior superior temporal gyrus, morphology of the superior temporal sulcus and gray matter volume of the inferior frontal gyrus. The impact of KIAA0319 gene on human brain development is mainly concentrated in the left temporal lobe, where abnormal KIAA0319 gene expression caused reduced gray matter in the left inferior temporal gyrus, middle temporal gyrus and fusiform gyrus, as well as reduced white matter volume in the left temporoparietal cortex. Abnormalities in KIAA0319 gene also led to decreased hemispheric asymmetry in the superior temporal sulcus. The above-mentioned brain regions are crucial for language and reading processing. It is analyzed that the abnormalities in the DD-associated KIAA0319 gene affect neuronal migration and morphology during brain development, resulting in abnormal development of subcortical structures (such as the medial geniculate nucleus and lateral geniculate nucleus) and cortical structures (including the left temporal cortex, temporoparietal cortex and fusiform gyrus) which are involved in human visual and auditory processing as well as language processing. Impairment of the medial geniculate nucleus affects the information transmission to the auditory cortex, leading to impaired phoneme processing. Abnormalities in the magnocellular layers within the lateral geniculate nucleus hinder the normal transmission of visual information to the visual cortex, affecting the dorsal visual pathway. The left temporal lobe is closely related to language and reading, and abnormalities in its gray matter and connections with other brain areas can affect the language and word processing. In summary, abnormalities in the KIAA0319 gene can partly explain current research findings on the cognitive and neural mechanisms of DD, providing a genetic basis for theoretical models related to DD (such as general sensorimotor theory and the magnocellular theory). However, the mechanism of developmental dyslexia is complex, and there are mutual influences between different DD-associated genes and between genes and the environment, which require further exploration.

KIAA0319 Genotype Predicts the Number of Past Concussions in a Division I Football Team: A Pilot Study.

This candidate gene study evaluated the relationship of a past history of concussion with single nucleotide polymorphisms (SNPs) in nine genes in a small cohort (N = 87) of a nationally ranked Division I football team. Genes and SNPs studied were selected based on their published connection to brain injury and brain development, as well as impulsivity. We used multinomial logistic regression analysis (MLRA) to quantify how well genotype predicted the number of previously diagnosed concussions (three categories: none, one, two or more), while covarying race and number of years participating in football. The rs4504469 SNP for KIAA0319 was the only locus that significantly predicted number of previously diagnosed concussions (p = 0.005, meeting Bonferroni correction for multiple comparisons). The KIAA0319 results raise the hypothesis that having the CT or TT genotype of KIAA0319 may be predictive of a lower incidence of previously diagnosed concussion. This finding raises a number of hypotheses for future pre-clinical research, particularly whether alterations in neural organization related to KIAA0319 rs4504469 lead to reduced susceptibility for lasting head trauma, or greater resilience in the face of repeated subconcussive injury.

The dyslexia susceptibility KIAA0319 gene shows a specific expression pattern during zebrafish development supporting a role beyond neuronal migration.

Dyslexia is a common neurodevelopmental disorder caused by a significant genetic component. The KIAA0319 gene is one of the most robust dyslexia susceptibility factors but its function remains poorly understood. Initial RNA-interference studies in rats suggested a role in neuronal migration whereas subsequent work with double knock-out mouse models for both Kiaa0319 and its paralogue Kiaa0319-like reported effects in the auditory system but not in neuronal migration. To further understand the role of KIAA0319 during neurodevelopment, we carried out an expression study of its zebrafish orthologue at different embryonic stages. We used different approaches including RNAscope in situ hybridization combined with light-sheet microscopy. The results show particularly high expression during the first few hours of development. Later, expression becomes localized in well-defined structures. In addition to high expression in the brain, we report for the first time expression in the eyes and the notochord. Surprisingly, kiaa0319-like, which generally shows a similar expression pattern to kiaa0319, was not expressed in the notochord suggesting a distinct role for kiaa0319 in this structure. This observation was supported by the identification of notochord enhancers enriched upstream of the KIAA0319 transcription start site, in both zebrafish and humans. This study supports a developmental role for KIAA0319 in the brain as well as in other developing structures, particularly in the notochord which, is key for establishing body patterning in vertebrates.

Increased variability of stimulus-driven cortical responses is associated with genetic variability in children with and without dyslexia.

Individuals with dyslexia exhibit increased brainstem variability in response to sound. It is unknown as to whether increased variability extends to neocortical regions associated with audition and reading, extends to visual stimuli, and whether increased variability characterizes all children with dyslexia or, instead, a specific subset of children. We evaluated the consistency of stimulus-evoked neural responses in children with (N = 20) or without dyslexia (N = 12) as measured by magnetoencephalography (MEG). Approximately half of the children with dyslexia had significantly higher levels of variability in cortical responses to both auditory and visual stimuli in multiple nodes of the reading network. There was a significant and positive relationship between the number of risk alleles at rs6935076 in the dyslexia-susceptibility gene KIAA0319 and the degree of neural variability in primary auditory cortex across all participants. This gene has been linked with neural variability in rodents and in typical readers. These findings indicate that unstable representations of auditory and visual stimuli in auditory and other reading-related neocortical regions are present in a subset of children with dyslexia and support the link between the gene KIAA0319 and the auditory neural variability across children with or without dyslexia.

KIAA0319 promoter DNA methylation predicts dichotic listening performance in forced-attention conditions.

Language lateralization is one of the most prominent examples of functional hemispheric asymmetries. Previous studies indicate a significant contribution of factors not related to DNA sequence variation on the development of language lateralization, but the molecular processes underlying this relation are unclear. The Brandler-Paracchini model of hemispheric asymmetries assumes that genes involved in the establishment of ciliogenesis and bodily asymmetries also affect functional hemispheric asymmetries. Thus, genes implicated in this model represent a key target for epigenetic modulation of language lateralization. Here, we analyzed DNA methylation in the KIAA0319 (a gene involved in dyslexia and ciliogenesis) promoter region to investigate whether epigenetic markers of language lateralization can be identified in non-neuronal tissue. We found sex-specific effects of DNA methylation in single CpG sites on language lateralization in the forced-left (FL) and the forced-right (FR), but not on language lateralization in the non-forced (NF) condition of the dichotic listening task. These findings suggest that DNA methylation patterns in the KIAA0319 promoter region might be associated with cognitive control processes that are necessary to perform well in the forced-attention conditions. Furthermore, the assumption of an association between genes involved in ciliogenesis and the ontogenesis of functional hemispheric asymmetries is supported.