Browsing by Subject "READING-DISABILITY"

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  • Tammimies, Kristiina; Bieder, Andrea; Lauter, Gilbert; Sugiaman-Trapman, Debora; Torchet, Rachel; Hokkanen, Marie-Estelle; Burghoorn, Jan; Castrén, Eero; Kere, Juha; Tapia-Paez, Isabel; Swoboda, Peter (2016)
    DYX1C1, DCDC2, and KIAA0319 are three of the most replicated dyslexia candidate genes (DCGs). Recently, these DCGs were implicated in functions at the cilium. Here, we investigate the regulation of these DCGs by Regulatory Factor X transcription factors (RFX TFs), a gene family known for transcriptionally regulating ciliary genes. We identify conserved X-box motifs in the promoter regions of DYX1C1, DCDC2, and KIAA0319 and demonstrate their functionality, as well as the ability to recruit RFX TFs using reporter gene and electrophoretic mobility shift assays. Furthermore, we uncover a complex regulation pattern between RFX1, RFX2, and RFX3 and their significant effect on modifying the endogenous expression of DYX1C1 and DCDC2 in a human retinal pigmented epithelial cell line immortalized with hTERT (hTERT-RPE1). In addition, induction of ciliogenesis increases the expression of RFX TFs and DCGs. At the protein level, we show that endogenous DYX1C1 localizes to the base of the cilium, whereas DCDC2 localizes along the entire axoneme of the cilium, thereby validating earlier localization studies using overexpression models. Our results corroborate the emerging role of DCGs in ciliary function and characterize functional noncoding elements, X-box promoter motifs, in DCG promoter regions, which thus can be targeted for mutation screening in dyslexia and ciliopathies associated with these genes.
  • Gialluisi, Alessandro; Andlauer, Till F. M.; Mirza-Schreiber, Nazanin; Moll, Kristina; Becker, Jessica; Hoffmann, Per; Ludwig, Kerstin U.; Czamara, Darina; St Pourcain, Beate; Brandler, William; Honbolygo, Ferenc; Toth, Denes; Csepe, Valeria; Huguet, Guillaume; Morris, Andrew P.; Hulslander, Jacqueline; Willcutt, Erik G.; DeFries, John C.; Olson, Richard K.; Smith, Shelley D.; Pennington, Bruce F.; Vaessen, Anniek; Maurer, Urs; Lyytinen, Heikki; Peyrard-Janvid, Myriam; Leppanen, Paavo H. T.; Brandeis, Daniel; Bonte, Milene; Stein, John F.; Talcott, Joel B.; Fauchereau, Fabien; Wilcke, Arndt; Francks, Clyde; Bourgeron, Thomas; Monaco, Anthony P.; Ramus, Franck; Landerl, Karin; Kere, Juha; Scerri, Thomas S.; Paracchini, Silvia; Fisher, Simon E.; Schumacher, Johannes; Noethen, Markus M.; Mueller-Myhsok, Bertram; Schulte-Koerne, Gerd (2019)
    Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p <1 x 10(-8)) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 x 10(-9)), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 x 10(-8)). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 x 10(-8)) and with all the cognitive traits tested (p = 3.07 x 10(-8)), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p similar to [10(-5)-10(-7)]) and negatively associated with ADHD PRS (p similar to [10(-8)-10(-17)]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
  • Einarsdottir, Elisabet; Svensson, Idor; Darki, Fahimeh; Peyrard-Janvid, Myriam; Lindvall, Jessica M.; Ameur, Adam; Jacobsson, Christer; Klingberg, Torkel; Kere, Juha; Matsson, Hans (2015)
    Developmental dyslexia is the most common learning disorder in children. Problems in reading and writing are likely due to a complex interaction of genetic and environmental factors, resulting in reduced power of studies of the genetic factors underlying developmental dyslexia. Our approach in the current study was to perform exome sequencing of affected and unaffected individuals within an extended pedigree with a familial form of developmental dyslexia. We identified a two-base mutation, causing a p.R229L amino acid substitution in the centrosomal protein 63 kDa (CEP63), co-segregating with developmental dyslexia in this pedigree. This mutation is novel, and predicted to be highly damaging for the function of the protein. 3D modelling suggested a distinct conformational change caused by the mutation. CEP63 is localised to the centrosome in eukaryotic cells and is required for maintaining normal centriole duplication and control of cell cycle progression. We found that a common polymorphism in the CEP63 gene had a significant association with brain white matter volume. The brain regions were partly overlapping with the previously reported region influenced by polymorphisms in the dyslexia susceptibility genes DYX1C1 and KIAA0319. We hypothesise that CEP63 is particularly important for brain development and might control the proliferation and migration of cells when those two events need to be highly coordinated.
  • Arrhenius, Bianca; Gyllenberg, David; Chudal, Roshan; Lehti, Venla; Sucksdorff, Minna; Sourander, Ona; Virtanen, Juha-Pekka; Torsti, Jutta; Sourander, Andre (2018)
    Background: Broadly defined learning and coordination disorders (LCDs) are common in the population and have previously been associated with familial social risk factors and male sex. However, comprehensive nationwide studies of these risk factors in LCD subgroups are lacking. Our objective was to assess different LCDs in relation to sex and maternal education, marital status and socioeconomic status based on occupation. Methods: We conducted a nationwide register-based study. The following diagnoses were identified from the Finnish Hospital Discharge Register (FHDR) according to the ICD-10 (n = 28,192): speech disorders (F80), scholastic disorders (F81), motor and coordination disorders (F82) and mixed developmental disorder (F83). To study cumulative incidence and male: female ratios of service use of LCDs, we used a cohort design among all Finnish children born singleton 1996-2007 (n = 690,654); to study social risk factors, we used a nested case-control design with extensive register data on both cases and matched controls (n = 106,616). Results: The cumulative incidence was 4.7% for any LCD by age 15 and the changes in cumulative incidence over time were minor. The male: female ratios were 2.2-3.0 across LCD subgroups. Learning and coordination disorders were more common in households with lower maternal education, socioeconomic status based on occupation and among children with single mothers at the time of birth; the odds ratios (OR) for any LCD were 1.2-1.9 across risk factors. The odds for LCD diagnosis increased linearly with the number of social risk factors, except for coordination disorder. The effect size of three risk factors was highest in the group with mixed or multiple LCDs; OR 3.76 (95% CI 3.31-4.28). Conclusions: Multiple social risk factors increase the odds for multiple, more comprehensive learning difficulties. The findings have implications for service planning, as early identification and interventions of learning and coordination disorders might reduce related long-term social adversities.
  • Lobier, Muriel A.; Peyrin, Carole; Pichat, Cedric; Le Bas, Jean-Francois; Valdois, Sylviane (2014)