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At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum P = 0.002 for non-word reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level., (© The Author(s) 2021. Published by Oxford University Press.)

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation., (© The Author 2016. Published by Oxford University Press.)

Approximately 90% of humans are right-handed. Handedness is a heritable trait, yet the genetic basis is not well understood. Here we report a genome-wide association study for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)]. The most highly associated marker, rs11855415 (P = 4.7 × 10(-7)), is located within PCSK6. Two independent cohorts with RD show the same trend, with the minor allele conferring greater relative right-hand skill. Meta-analysis of all three RD samples is genome-wide significant (n = 744, P = 2.0 × 10(-8)). Conversely, in the general population (n = 2666), we observe a trend towards reduced laterality of hand skill for the minor allele (P = 0.0020). These results provide molecular evidence that cerebral asymmetry and dyslexia are linked. Furthermore, PCSK6 is a protease that cleaves the left-right axis determining protein NODAL. Functional studies of PCSK6 promise insights into mechanisms underlying cerebral lateralization and dyslexia.

The KIAA0319 gene has been recently associated with developmental dyslexia and shown to be involved in neuronal migration. The deduced KIAA0319 protein contains several polycystic kidney disease (PKD) domains which may mediate the interaction between neurons and glial fibres during neuronal migration. We have previously reported the presence of several alternative splicing variants, some of which are predicted to affect the deduced protein. In this study, we over-expressed constructs containing the main form (A) and two alternative variants (B and C) of KIAA0319. We show that the full-length KIAA0319 (A) is a type I plasma membrane protein, a topology consistent with its proposed function in neuronal migration. The oligomeric status of KIAA0319 is mainly dimeric, and this condition depends on the cysteine-rich regions of the protein, especially the transmembrane (TM) domain and surrounding sequence. KIAA0319 is highly glycosylated in different mammalian cell lines. The central region including the PKD domains is N-glycosylated. Furthermore, a short fragment N-terminal to the PKD domains contains mucin-type O-glycosylation. The two alternative isoforms are soluble proteins lacking the TM domain and, interestingly, only isoform B is secreted. KIAA0319-deletion proteins lacking the TM domain were also secreted. These results suggest that KIAA0319 could be involved not only in cell-cell interactions, but also in signalling.

Neurofibrillary tangles composed of exon 10+ microtubule associated protein tau (MAPT) deposits are the characteristic feature of the neurodegenerative diseases progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). PSP, CBD and more recently Alzheimer's disease and Parkinson's disease, are associated with the MAPT H1 haplotype, but the relationship between genotype and disease remains unclear. Here, we investigate the hypothesis that H1 expresses more exon 10+ MAPT mRNA compared to the other haplotype, H2, leading to a greater susceptibility to neurodegeneration in H1 carriers. We performed allele-specific gene expression on two H1/H2 heterozygous human neuronal cell lines, and 14 H1/H2 heterozygous control individual post-mortem brain tissue from two brain regions. In both tissue culture and post-mortem brain tissue, we show that the MAPT H1 haplotype expresses significantly more exon 10+ MAPT mRNA than H2. In post-mortem brain tissue, we show that the total level of MAPT expression from H1 and H2 is not significantly different, but that the H1 chromosome expresses up to 1.43-fold more exon 10+ MAPT mRNA than H2 in the globus pallidus, a brain region highly affected by tauopathy (maximum exon 10+ MAPT H1:H2 transcript ratio=1.425, SD=0.205, P<0.0001), and up to 1.29-fold more exon 10+ MAPT mRNA than H2 in the frontal cortex (maximum exon 10+ MAPT H1:H2 transcript ratio=1.291, SD=0.315, P=0.006). These data may explain the increased susceptibility of H1 carriers to neurodegeneration and suggest a potential mechanism between MAPT genetic variability and the pathogenesis of neurodegenerative disease.

Dyslexia is one of the most prevalent childhood cognitive disorders, affecting approximately 5% of school-age children. We have recently identified a risk haplotype associated with dyslexia on chromosome 6p22.2 which spans the TTRAP gene and portions of THEM2 and KIAA0319. Here we show that in the presence of the risk haplotype, the expression of the KIAA0319 gene is reduced but the expression of the other two genes remains unaffected. Using in situ hybridization, we detect a very distinct expression pattern of the KIAA0319 gene in the developing cerebral neocortex of mouse and human fetuses. Moreover, interference with rat Kiaa0319 expression in utero leads to impaired neuronal migration in the developing cerebral neocortex. These data suggest a direct link between a specific genetic background and a biological mechanism leading to the development of dyslexia: the risk haplotype on chromosome 6p22.2 down-regulates the KIAA0319 gene which is required for neuronal migration during the formation of the cerebral neocortex.