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  • 1. Anthoni, Heidi
    et al.
    Zucchelli, Marco
    Matsson, Hans
    Müller-Myhsok, Bertram
    Fransson, Ingegerd
    Schumacher, Johannes
    Massinen, Satu
    Onkamo, Päivi
    Warnke, Andreas
    Griesemann, Heide
    Hoffmann, Per
    Nopola-Hemmi, Jaana
    Lyytinen, Heikki
    Schulte-Körne, Gerd
    Kere, Juha
    Nöthen, Markus M
    Peyrard-Janvid, Myriam
    A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia.2007In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 16, no 6, p. 667-77Article in journal (Refereed)
    Abstract [en]

    DYX3, a locus for dyslexia, resides on chromosome 2p11-p15. We have refined its location on 2p12 to a 157 kb region in two rounds of linkage disequilibrium (LD) mapping in a set of Finnish families. The observed association was replicated in an independent set of 251 German families. Two overlapping risk haplotypes spanning 16 kb were identified in both sample sets separately as well as in a joint analysis. In the German sample set, the odds ratio for the most significantly associated haplotype increased with dyslexia severity from 2.2 to 5.2. The risk haplotypes are located in an intergenic region between FLJ13391 and MRPL19/C2ORF3. As no novel genes could be cloned from this region, we hypothesized that the risk haplotypes might affect long-distance regulatory elements and characterized the three known genes. MRPL19 and C2ORF3 are in strong LD and were highly co-expressed across a panel of tissues from regions of adult human brain. The expression of MRPL19 and C2ORF3, but not FLJ13391, were also correlated with the four dyslexia candidate genes identified so far (DYX1C1, ROBO1, DCDC2 and KIAA0319). Although several non-synonymous changes were identified in MRPL19 and C2ORF3, none of them significantly associated with dyslexia. However, heterozygous carriers of the risk haplotype showed significantly attenuated expression of both MRPL19 and C2ORF3, as compared with non-carriers. Analysis of C2ORF3 orthologues in four non-human primates suggested different evolutionary rates for primates when compared with the out-group. In conclusion, our data support MRPL19 and C2ORF3 as candidate susceptibility genes for DYX3.

  • 2. Arkani, Samara
    et al.
    Cao, Jia
    Lundin, Johanna
    Nilsson, Daniel
    Källman, Thomas
    Barker, Gillian
    Holmdahl, Gundela
    Clementsson Kockum, Christina
    Matsson, Hans
    Nordenskjöld, Agneta
    Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort.2018In: Human genome variation, ISSN 2054-345X, Vol. 5, article id 18009Article in journal (Refereed)
    Abstract [en]

    gene is not a common genetic mechanism of BEEC development in the Swedish population.

  • 3.
    Dahlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Orlén, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Matsson, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lönnerholm, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gustavson, Karl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Multiple epiphyseal dysplasia: A clinical and genetic study of 12 cases in a Swedish 6-generation family2009In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 80, no 6, p. 711-715Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Multiple epiphyseal dysplasia (MED) is a common genetically and clinically heterogeneous skeletal dysplasia characterized by early-onset osteoarthritis, mainly in the hip and knee, and mild-to-moderate short stature. Here we report on a 6-generation MED family with 17 affected members. METHOD: The clinical and radiographic data on the 12 affected members still living were scrutinized. A structured inquiry comprising state of health and MED-related symptoms since birth up to the present time and the osteoarthritis outcome (KOOS) questionnaire were sent to all living family members with MED. The 5 known gene loci for autosomal dominant MED were analyzed for linkage, using fluorescence-labeled microsatellite markers. Linkage was ascertained with markers close to the COL9A2 gene, which was analyzed for mutations by sequencing. RESULTS: We identified an exon 3 donor splice mutation in the COL9A2 gene in all affected family members. Clinical, radiographic, and questionnaire data from affected family members suggested that MED caused by COL9A2 mutations starts in early childhood with knee pain accompanied by delayed ossification of femoral epiphyses. The disease then either stabilizes during puberty or progresses with additional joints becoming affected; joint surgery might be necessary. The progression of the disease also affects muscles, with increasing atrophy, resulting in muscle fatigue and pain. Muscular atrophy has not been reported earlier in cases with COL9A2 mutations. INTERPRETATION: In a patient with clinically suspected or verified MED, it is important to perform DNA-based analysis to identify a possible disease-causing mutation. This information can be used to carry out genetic risk assessment of other family members and to achieve an early and correct diagnosis in the children.

  • 4. Darki, Fahimeh
    et al.
    Massinen, Satu
    Salmela, Elina
    Matsson, Hans
    Peyrard-Janvid, Myriam
    Klingberg, Torkel
    Kere, Juha
    Human ROBO1 regulates white matter structure in corpus callosum.2017In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 222, no 2, p. 707-716Article in journal (Refereed)
    Abstract [en]

    The axon guidance receptor, Robo1, controls the pathfinding of callosal axons in mice. To determine whether the orthologous ROBO1 gene is involved in callosal development also in humans, we studied polymorphisms in the ROBO1 gene and variation in the white matter structure in the corpus callosum using both structural magnetic resonance imaging and diffusion tensor magnetic resonance imaging. We found that five polymorphisms in the regulatory region of ROBO1 were associated with white matter density in the posterior part of the corpus callosum pathways. One of the polymorphisms, rs7631357, was also significantly associated with the probability of connections to the parietal cortical regions. Our results demonstrate that human ROBO1 may be involved in the regulation of the structure and connectivity of posterior part of corpus callosum.

  • 5. Darki, Fahimeh
    et al.
    Peyrard-Janvid, Myriam
    Matsson, Hans
    Kere, Juha
    Klingberg, Torkel
    DCDC2 polymorphism is associated with left temporoparietal gray and white matter structures during development.2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 43, p. 14455-62Article in journal (Refereed)
    Abstract [en]

    Three genes, DYX1C1, DCDC2, and KIAA0319, have been previously associated with dyslexia, neuronal migration, and ciliary function. Three polymorphisms within these genes, rs3743204 (DYX1C1), rs793842 (DCDC2), and rs6935076 (KIAA0319) have also been linked to normal variability of left temporoparietal white matter volume connecting the middle temporal cortex to the angular and supramarginal gyri. Here, we assessed whether these polymorphisms are also related to the cortical thickness of the associated regions during childhood development using a longitudinal dataset of 76 randomly selected children and young adults who were scanned up to three times each, 2 years apart. rs793842 in DCDC2 was significantly associated with the thickness of left angular and supramarginal gyri as well as the left lateral occipital cortex. The cortex was significantly thicker for T-allele carriers, who also had lower white matter volume and lower reading comprehension scores. There was a negative correlation between white matter volume and cortical thickness, but only white matter volume predicted reading comprehension 2 years after scanning. These results show how normal variability in reading comprehension is related to gene, white matter volume, and cortical thickness in the inferior parietal lobe. Possibly, the variability of gray and white matter structures could both be related to the role of DCDC2 in ciliary function, which affects both neuronal migration and axonal outgrowth.

  • 6. Darki, Fahimeh
    et al.
    Peyrard-Janvid, Myriam
    Matsson, Hans
    Kere, Juha
    Klingberg, Torkel
    Three dyslexia susceptibility genes, DYX1C1, DCDC2, and KIAA0319, affect temporo-parietal white matter structure.2012In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 72, no 8, p. 671-6, article id S0006-3223(12)00445-3Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Volume and integrity of white matter correlate with reading ability, but the underlying factors contributing to this variability are unknown.

    METHODS: We investigated single nucleotide polymorphisms in three genes previously associated with dyslexia and implicated in neuronal migration (DYX1C1, DCDC2, KIAA0319) and white matter volume in a cohort of 76 children and young adults from the general population.

    RESULTS: We found that all three genes contained polymorphisms that were significantly associated with white matter volume in the left temporo-parietal region and that white matter volume influenced reading ability.

    CONCLUSIONS: The identified region contained white matter pathways connecting the middle temporal gyrus with the inferior parietal lobe. The finding links previous neuroimaging and genetic results and proposes a mechanism underlying variability in reading ability in both normal and impaired readers.

  • 7.
    Draptchinskaia, Natalia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustavsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Andersson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pettersson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Willig, Thiébaut-Noël
    Dianzani, Irma
    Ball, Sarah
    Tchernia, Gil
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Matsson, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Tentler, Dimitri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mohandas, Narla
    Carlsson, Birgit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia1999In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 21, no 2, p. 169-75Article in journal (Refereed)
    Abstract [en]

    Diamond-Blackfan anaemia (DBA) is a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors. The disease, previously mapped to human chromosome 19q13, is frequently associated with a variety of malformations. To identify the gene involved in DBA, we cloned the chromosome 19q13 breakpoint in a patient with a reciprocal X;19 chromosome translocation. The breakpoint occurred in the gene encoding ribosomal protein S19. Furthermore, we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations, as well as two intragenic deletions. These mutations are associated with clinical features that suggest a function for RPS19 in erythropoiesis and embryogenesis.

  • 8. Dumontheil, Iroise
    et al.
    Roggeman, Chantal
    Ziermans, Tim
    Peyrard-Janvid, Myriam
    Matsson, Hans
    Kere, Juha
    Klingberg, Torkel
    Influence of the COMT genotype on working memory and brain activity changes during development.2011In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 70, no 3, p. 222-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Valine158Methionine (Val158Met) polymorphism of the COMT gene leads to lower enzymatic activity and higher dopamine availability in Met carriers. The Met allele is associated with better performance and reduced prefrontal cortex activation during working memory (WM) tasks in adults. Dopaminergic system changes during adolescence may lead to a reduction of basal dopamine levels, potentially affecting Met allele benefits during development.

    METHODS: We investigated the association of COMT genotype with behavioral (n = 322) and magnetic resonance imaging data (n = 81-84) collected during performance of a visuospatial WM task and potential changes in these effects during development (reflected in age × genotype interactions). Data were collected from a cross-sectional and longitudinal typically developing sample of 6- to 20-year-olds.

    RESULTS: Visuospatial WM capacity exhibited an age × genotype interaction, with a benefit of the Met allele emerging after 10 years of age. There was a parallel age × genotype interaction on WM-related activation in the right inferior frontal gyrus and intraparietal sulcus (IPS), with increases in activation with age in the Val/Val group only. Main effects of COMT genotype were also observed in the IPS, with greater gray matter volumes bilaterally and greater right IPS activation in the Val/Val group compared with the Met carriers.

    CONCLUSIONS: These results suggest that COMT genotype effects on WM brain activity and behavior are not static during development. The full developmental picture should be considered when trying to understand the impact of genetic polymorphisms on the mature cognition of healthy adult or psychiatric populations.

  • 9. Einarsdottir, Elisabet
    et al.
    Peyrard-Janvid, Myriam
    Darki, Fahimeh
    Tuulari, Jetro J
    Merisaari, Harri
    Karlsson, Linnea
    Scheinin, Noora M
    Saunavaara, Jani
    Parkkola, Riitta
    Kantojärvi, Katri
    Ämmälä, Antti-Jussi
    Yiu-Lin Yu, Nancy
    Matsson, Hans
    Nopola-Hemmi, Jaana
    Karlsson, Hasse
    Paunio, Tiina
    Klingberg, Torkel
    Leinonen, Eira
    Kere, Juha
    Identification of NCAN as a candidate gene for developmental dyslexia.2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 9294Article in journal (Refereed)
    Abstract [en]

    A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. Analysis of coding variants from two affected individuals identified rs146011974G > A (Ala1039Thr), a rare variant within the NCAN gene co-segregating with DD in the pedigree. This variant prompted us to consider this gene as a putative candidate for DD. The RNA expression pattern of the NCAN gene in human tissues was highly correlated (R > 0.8) with that of the previously suggested DD susceptibility genes KIAA0319, CTNND2, CNTNAP2 and GRIN2B. We investigated the association of common variation in NCAN to brain structures in two data sets: young adults (Brainchild study, Sweden) and infants (FinnBrain study, Finland). In young adults, we found associations between a common genetic variant in NCAN, rs1064395, and white matter volume in the left and right temporoparietal as well as the left inferior frontal brain regions. In infants, this same variant was found to be associated with cingulate and prefrontal grey matter volumes. Our results suggest NCAN as a new candidate gene for DD and indicate that NCAN variants affect brain structure.

  • 10.
    Entesarian, Miriam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Matsson, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bergendal, Birgitta
    Olson, Lena
    Arakaki, Rieko
    Hayashi, Yoshio
    Ohuchi, Hideyo
    Falahat, Babak
    Bolstad, Anne Isine
    Jonsson, Roland
    Wahren-Herlenius, Marie
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mutations in the gene encoding fibroblast growth factor 10 are associated with2005In: Nat Genet, ISSN 1061-4036, Vol. 37, no 2, p. 125-7Article in journal (Refereed)
    Abstract [en]

    Autosomal dominant aplasia of lacrimal and salivary glands (ALSG; OMIM 180920 and OMIM 103420) is a rare condition characterized by irritable eyes and dryness of the mouth. We mapped ALSG to 5p13.2-5q13.1, which coincides with the gene fibroblast growth factor 10 (FGF10). In two extended pedigrees, we identified heterozygous mutations in FGF10 in all individuals with ALSG. Fgf10(+/-) mice have a phenotype similar to ALSG, providing a model for this disorder. We suggest that haploinsufficiency for FGF10 during a crucial stage of development results in ALSG.

  • 11. Fadista, João
    et al.
    Lund, Marie
    Skotte, Line
    Geller, Frank
    Nandakumar, Priyanka
    Chatterjee, Sumantra
    Matsson, Hans
    Granström, Anna Löf
    Wester, Tomas
    Salo, Perttu
    Virtanen, Valtter
    Carstensen, Lisbeth
    Bybjerg-Grauholm, Jonas
    Hougaard, David Michael
    Pakarinen, Mikko
    Perola, Markus
    Nordenskjöld, Agneta
    Chakravarti, Aravinda
    Melbye, Mads
    Feenstra, Bjarke
    Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus.2018In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 4, p. 561-569Article in journal (Refereed)
    Abstract [en]

    ; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.

  • 12. Flygare, Johan
    et al.
    Kiefer, Thomas
    Miyake, Koichi
    Utsugisawa, Taiju
    Hamaguchi, Isao
    Da Costa, Lydie
    Richter, Johan
    Davey, Edward J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Matsson, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wiznerowicz, Maciej
    Trono, Didier
    Karlsson, Stefan
    Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, no 12, p. 4627-4634Article in journal (Refereed)
    Abstract [en]

    Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein S19 (RPS19) gene. To study effects of RPS19 deficiency in hematopoiesis we transduced CD34+ umbilical cord blood (CB) and bone marrow (BM) cells with 3 lentiviral vectors expressing small interfering RNA (siRNA) against RPS19 and 1 scrambled control vector. All vectors also express green fluorescent protein (GFP). Transduction with the siRNA vectors reduced RPS19 mRNA levels to various degrees, which resulted in erythroid defects, correlating to the degree of RPS19 down-regulation, and was rescued by expression of an siRNA-resistant RPS19 transcript. Erythroid colony formation capacity conjointly decreased with RPS19 levels in CD34+ CB and BM cells. In liquid culture supporting erythroid differentiation, RPS19-silenced as well as DBA patient CD34+ cells exhibited reduced proliferative capacity and impaired erythroid differentiation resulting in fewer erythroid colony-forming units (CFU-Es). When assaying myeloid development, a less pronounced influence on proliferation was seen. This study shows for the first time that RPS19 silencing decreases the proliferative capacity of hematopoietic progenitors and leads to a defect in erythroid development.

  • 13. Goumidi, Louisa
    et al.
    Dahlman-Wright, Karin
    Tapia-Paez, Isabel
    Matsson, Hans
    Pasquier, Florence
    Amouyel, Philippe
    Kere, Juha
    Lambert, Jean-Charles
    Meirhaeghe, Aline
    Study of estrogen receptor-α and receptor-β gene polymorphisms on Alzheimer's disease.2011In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 26, no 3, p. 431-9Article in journal (Refereed)
    Abstract [en]

    Estrogen treatment can modulate the risk for developing dementia in women. Therefore, single nucleotide polymorphisms (SNPs) in the estrogen receptor genes may constitute genetic susceptibility factors to Alzheimer's disease (AD). Thus, we investigated the impact of the genetic variability of the estrogen receptor α 1 (ESR1) and estrogen receptor α 2 (ESR2) genes on late onset AD risk. We analyzed 39 SNPs in ESR1 and 5 SNPs in ESR2 in a French case-control study of sporadic AD (1007 cases/647 controls). Individuals carrying the minor allele of rs7450824 had a lower risk of AD than homozygous subjects for the major allele (age, gender, and APOE ε4 allele adjusted odds ratio = 0.71 [0.57-0.89], p = 0.003). However, this association did not resist Bonferroni correction for multiple testing (p-threshold < 0.001). Consistently, no significant association could be detected when considering age of onset. We also tested for possible interactions between the ESR SNPs and APOE status (ε4 allele) or gender but no significant interaction could be observed. Even after stratifying the sample on APOE status or gender, no significant association with AD risk could be detected. Finally, we searched for potential gene-gene interactions between ESR1 and ESR2 SNPs but no significant interaction could be detected. Our results reinforce the notion that SNPs in the ESR1 or ESR2 genes do not seem to play a major role in the genetic susceptibility of AD.

  • 14.
    Gustavsson, Peter
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Klar, Joakim
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Matsson, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Forestier, Erik
    Henter, Jan-Inge
    Rao, Sreedhar
    Seip, Martin
    Skeppner, Gunnar
    Dahl, Niklas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Familial transient erythroblastopenia of childhood is associated with the chromosome2002In: Br J Haematol, ISSN 0007-1048, Vol. 119, no 1, p. 261-4Article in journal (Refereed)
    Abstract [en]

    Transient erythroblastopenia of childhood (TEC) is a rare condition, which at onset may be difficult to distinguish from Diamond-Blackfan anaemia (DBA). We have previously shown that mutations in the ribosomal protein S19 gene (RPS19) cause DBA. In order to clarify whether TEC and DBA are allelic, we investigated the segregation of markers spanning the RPS19 gene region on chromosome 19q13.2 and performed sequence analysis of all exons in the RPS19 gene in seven TEC sibling pairs. Linkage analysis supported allelism for TEC and DBA at the RPS19 gene locus and implies molecular mechanisms other than structural mutations in the RPS19 gene.

  • 15. Hofmeister, Wolfgang
    et al.
    Nilsson, Daniel
    Topa, Alexandra
    Anderlid, Britt-Marie
    Darki, Fahimeh
    Matsson, Hans
    Tapia Páez, Isabel
    Klingberg, Torkel
    Samuelsson, Lena
    Wirta, Valtteri
    Vezzi, Francesco
    Kere, Juha
    Nordenskjöld, Magnus
    Syk Lundberg, Elisabeth
    Lindstrand, Anna
    CTNND2-a candidate gene for reading problems and mild intellectual disability.2015In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 52, no 2, p. 111-22Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders.

    METHODS AND RESULTS: Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22;q24) and t(5;18)(p15;q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patient's mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon.

    CONCLUSIONS: Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.

  • 16. Huang, Jiaqi
    et al.
    Löhr, Johannes-Matthias
    Nilsson, Magnus
    Segersvärd, Ralf
    Matsson, Hans
    Verbeke, Caroline
    Heuchel, Rainer
    Kere, Juha
    Iafrate, A John
    Zheng, Zongli
    Ye, Weimin
    Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma.2015In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 61, no 11, p. 1408-16Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Variant profiling is crucial for developing personalized treatment and elucidating the etiology of this disease.

    METHODS: Patients with PDAC undergoing surgery from 2007 to 2012 (n = 73) were followed from diagnosis until death or the end of the study. We applied an anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) method to a panel of 65 selected genes and assessed analytical performance by sequencing a quantitative multiplex DNA reference standard. In clinical PDAC samples, detection of low-level KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations was validated by allele-specific PCR and digital PCR. We compared overall survival of patients according to KRAS mutation status by log-rank test and applied logistic regression to evaluate the association between smoking and tumor variant types.

    RESULTS: The AMP-based NGS method could detect variants with allele frequencies as low as 1% given sufficient sequencing depth (>1500×). Low-frequency KRAS G12 mutations (allele frequency 1%-5%) were all confirmed by allele-specific PCR and digital PCR. The most prevalent genetic alterations were in KRAS (78% of patients), TP53 (tumor protein p53) (25%), and SMAD4 (SMAD family member 4) (8%). Overall survival in T3-stage PDAC patients differed among KRAS mutation subtypes (P = 0.019). Transversion variants were more common in ever-smokers than in never-smokers (odds ratio 5.7; 95% CI 1.2-27.8).

    CONCLUSIONS: The AMP-based NGS method is applicable for profiling tumor variants. Using this approach, we demonstrated that in PDAC patients, KRAS mutant subtype G12V is associated with poorer survival, and that transversion variants are more common among smokers.

  • 17. Karimi, Mohsen
    et al.
    Nilsson, Christer
    Dimitriou, Marios
    Jansson, Monika
    Matsson, Hans
    Unneberg, Per
    Lehmann, Sören
    Kere, Juha
    Hellström-Lindberg, Eva
    High-throughput mutational screening adds clinically important information in myelodysplastic syndromes and secondary or therapy-related acute myeloid leukemia.2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, no 6, p. e223-5Article in journal (Refereed)
  • 18. Massinen, Satu
    et al.
    Hokkanen, Marie-Estelle
    Matsson, Hans
    Tammimies, Kristiina
    Tapia-Páez, Isabel
    Dahlström-Heuser, Vanina
    Kuja-Panula, Juha
    Burghoorn, Jan
    Jeppsson, Kristian E
    Swoboda, Peter
    Peyrard-Janvid, Myriam
    Toftgård, Rune
    Castrén, Eero
    Kere, Juha
    Increased expression of the dyslexia candidate gene DCDC2 affects length and signaling of primary cilia in neurons.2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, article id e20580Article in journal (Refereed)
    Abstract [en]

    DCDC2 is one of the candidate susceptibility genes for dyslexia. It belongs to the superfamily of doublecortin domain containing proteins that bind to microtubules, and it has been shown to be involved in neuronal migration. We show that the Dcdc2 protein localizes to the primary cilium in primary rat hippocampal neurons and that it can be found within close proximity to the ciliary kinesin-2 subunit Kif3a. Overexpression of DCDC2 increases ciliary length and activates Shh signaling, whereas downregulation of Dcdc2 expression enhances Wnt signaling, consistent with a functional role in ciliary signaling. Moreover, DCDC2 overexpression in C. elegans causes an abnormal neuronal phenotype that can only be seen in ciliated neurons. Together our results suggest a potential role for DCDC2 in the structure and function of primary cilia.

  • 19. Massinen, Satu
    et al.
    Tammimies, Kristiina
    Tapia-Páez, Isabel
    Matsson, Hans
    Hokkanen, Marie-Estelle
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Castrén, Eero
    Gustafsson, Jan-Åke
    Treuter, Eckardt
    Kere, Juha
    Functional interaction of DYX1C1 with estrogen receptors suggests involvement of hormonal pathways in dyslexia2009In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, no 15, p. 2802-2812Article in journal (Refereed)
    Abstract [en]

    Dyslexia, or specific reading disability, is the unexpected failure in learning to read and write when intelligence and senses are normal. One of the susceptibility genes, DYX1C1, has been implicated in neuronal migration, but little is known about its interactions and functions. As DYX1C1 was suggested to interact with the U-box protein CHIP (carboxy terminus of Hsc70-interacting protein), which also participates in the degradation of estrogen receptors alpha (ERalpha) and beta (ERbeta), we hypothesized that the effects of DYX1C1 might be at least in part mediated through the regulation of ERs. ERs have shown to be important in brain development and cognitive functions. Indeed, we show that DYX1C1 interacts with both ERs in the presence of 17beta-estradiol, as determined by co-localization, co-immunoprecipitation and proximity ligation assays. Protein levels of endogenous ERalpha or exogenous ERbeta were reduced upon over-expression of DYX1C1, resulting in decreased transcriptional responses to 17beta-estradiol. Furthermore, we detected in vivo complexes of DYX1C1 with ERalpha or ERbeta at endogenous levels along neurites of primary rat hippocampal neurons. Taken together, our data suggest that DYX1C1 is involved in the regulation of ERalpha and ERbeta, and may thus affect the brain development and regulate cognitive functions. These findings provide novel insights into the function of DYX1C1 and link neuronal migration and developmental dyslexia to the estrogen-signaling effects in the brain.

  • 20.
    Matsson, H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboratory.
    Davey, EJ
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboratory.
    Frojmark, AS
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboraory.
    Miyake, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboratory.
    Utsugisawa, T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboratory.
    Flygare, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboratory.
    Zahou, E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboratory.
    Byman, I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboratory.
    Landin, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboratory.
    Ronquist, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Klinisk kemi.
    Karlsson, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboratory.
    Dahl, N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. The Rudbeck Laboratory.
    Erythropoiesis in the Rps19 disrupted mouse: Analysis of erythropoietin response and biochemical markers for Diamond-Blackfan anemia.2006In: Blood Cells Mol Dis, Vol. 36, no 2, p. 259-264Article in journal (Refereed)
    Abstract [en]

    The human ribosomal protein S19 gene (RPS19) is mutated in approximately 20% of patients with Diamond-Blackfan anemia (DBA), a congenital disease with a specific defect in erythropoiesis. The clinical expression of DBA is highly variable, and subclinical phenotypes may be revealed by elevated erythrocyte deaminase (eADA) activity only. In mice, complete loss of Rps19 results in early embryonic lethality whereas Rps19+/− mice are viable and without major abnormalities including the hematopoietic system. We have performed a detailed analysis of the Rps19+/− mice. We estimated the Rps19 levels in hematopoietic tissues and we analyzed erythrocyte deaminase activity and globin isoforms which are used as markers for DBA. The effect of a disrupted Rps19 allele on a different genetic background was investigated as well as the response to erythropoietin (EPO). From our results, we argue that the loss of one Rps19 allele in mice is fully compensated for at the transcriptional level with preservation of erythropoiesis.

  • 21.
    Matsson, Hans
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Rudbeck Laboratory.
    Davey, Edward J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Rudbeck Laboratory.
    Draptchinskaia, Natalia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Rudbeck Laboratory.
    Hamaguchi, Isao
    Ooka, Andreas
    Leveen, Per
    Forsberg, Erik
    Karlsson, Stefan
    Dahl, Niklas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Rudbeck Laboratory.
    Targeted disruption of the ribosomal protein S19 gene is lethal prior to implantation.2004In: Mol Cell Biol, ISSN 0270-7306, Vol. 24, no 9, p. 4032-7Article in journal (Refereed)
    Abstract [en]

    The ribosomal protein S19 (RPS19) is located in the small (40S) subunit and is one of 79 ribosomal proteins. The gene encoding RPS19 is mutated in approximately 25% of patients with Diamond-Blackfan anemia, which is a rare congenital erythroblastopenia. Affected individuals present with decreased numbers or the absence of erythroid precursors in the bone marrow, and associated malformations of various organs are common. We produced C57BL/6J mice with a targeted disruption of murine Rps19 to study its role in erythropoiesis and development. Mice homozygous for the disrupted Rps19 were not identified as early as the blastocyst stage, indicating a lethal effect. In contrast, mice heterozygous for the disrupted Rps19 allele have normal growth and organ development, including that of the hematopoietic system. Our findings indicate that zygotes which are Rps19(-/-) do not form blastocysts, whereas one normal Rps19 allele in C57BL/6J mice is sufficient to maintain normal ribosomal and possibly extraribosomal functions.

  • 22.
    Matsson, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Eason, Jacqueline
    Bookwalter, Carol S.
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustavsson, Peter
    Sunnegårdh, Jan
    Enell, Henrik
    Jonzon, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Vikkula, Miikka
    Gutierrez, Ilse
    Granados-Riveron, Javier
    Pope, Mark
    Bu'Lock, Frances
    Cox, Jane
    Robinson, Thelma E.
    Song, Feifei
    Brook, David J.
    Marston, Steven
    Trybus, Kathleen M.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Alpha-cardiac actin mutations produce atrial septal defects2008In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, no 2, p. 256-265Article in journal (Refereed)
    Abstract [en]

    Atrial septal defect (ASD) is one of the most frequent congenital heart defects (CHDs) with a variable phenotypic effect depending on the size of the septal shunt. We identified two pedigrees comprising 20 members segregating isolated autosomal dominant secundum ASD. By genetic mapping, we identified the gene-encoding alpha-cardiac actin (ACTC1), which is essential for cardiac contraction, as the likely candidate. A mutation screen of the coding regions of ACTC1 revealed a founder mutation predicting an M123V substitution in affected individuals of both pedigrees. Functional analysis of ACTC1 with an M123V substitution shows a reduced affinity for myosin, but with retained actomyosin motor properties. We also screened 408 sporadic patients with CHDs and identified a case with ASD and a 17-bp deletion in ACTC1 predicting a non-functional protein. Morpholino (MO) knockdown of ACTC1 in chick embryos produces delayed looping and reduced atrial septa, supporting a developmental role for this protein. The combined results indicate, for the first time, that ACTC1 mutations or reduced ACTC1 levels may lead to ASD without signs of cardiomyopathy.

  • 23. Matsson, Hans
    et al.
    Huss, Mikael
    Persson, Helena
    Einarsdottir, Elisabet
    Tiraboschi, Ettore
    Nopola-Hemmi, Jaana
    Schumacher, Johannes
    Neuhoff, Nina
    Warnke, Andreas
    Lyytinen, Heikki
    Schulte-Körne, Gert
    Nöthen, Markus M
    Leppänen, Paavo H T
    Peyrard-Janvid, Myriam
    Kere, Juha
    Polymorphisms in DCDC2 and S100B associate with developmental dyslexia.2015In: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 60, no 7, p. 399-401Article in journal (Refereed)
    Abstract [en]

    Genetic studies of complex traits have become increasingly successful as progress is made in next-generation sequencing. We aimed at discovering single nucleotide variation present in known and new candidate genes for developmental dyslexia: CYP19A1, DCDC2, DIP2A, DYX1C1, GCFC2 (also known as C2orf3), KIAA0319, MRPL19, PCNT, PRMT2, ROBO1 and S100B. We used next-generation sequencing to identify single-nucleotide polymorphisms in the exons of these 11 genes in pools of 100 DNA samples of Finnish individuals with developmental dyslexia. Subsequent individual genotyping of those 100 individuals, and additional cases and controls from the Finnish and German populations, validated 92 out of 111 different single-nucleotide variants. A nonsynonymous polymorphism in DCDC2 (corrected P = 0.002) and a noncoding variant in S100B (corrected P = 0.016) showed a significant association with spelling performance in families of German origin. No significant association was found for the variants neither in the Finnish case-control sample set nor in the Finnish family sample set. Our findings further strengthen the role of DCDC2 and implicate S100B, in the biology of reading and spelling.

  • 24.
    Matsson, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Draptchinskaia, Natalia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustavsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlsson, Birgit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bowers, Daniel
    de Bont, Eveline
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Truncating ribosomal protein S19 mutations and variable clinical expression in Diamond-Blackfan anemia1999In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 105, no 5, p. 496-500Article in journal (Refereed)
    Abstract [en]

    Diamond-Blackfan anemia (DBA) is a rare constitutional erythroblastopenia characterized by a specific defect in erythroid differentiation. Recently, mutations in the gene encoding ribosomal protein (RP) S19 were found in a subset of patients with the disease. To characterize further RPS19 mutations and to investigate genotype-phenotype relationships, we screened this gene for mutations in patients with DBA by direct sequencing and Southern-blot analysis. Four novel mutations were identified. A G120A nonsense mutation resulting in a stop at codon 33, a C302T nonsense mutation introducing a premature stop at codon 84, and a 327delG which results in a frame shift at codon 103. A fourth and more complex mutation (TT157-158AA, 160insCT) resulting in a Leu45Gln and a frame shift from codon 47 was found in three affected family members with variable phenotypes. The different clinical expression for identical mutations suggest the presence of other modulating factors for the disease. The mutations presented here further support the role of RPS19 in erythropoietic differentiation and proliferation.

  • 25. Matsson, Hans
    et al.
    Tammimies, Kristiina
    Zucchelli, Marco
    Anthoni, Heidi
    Onkamo, Päivi
    Nopola-Hemmi, Jaana
    Lyytinen, Heikki
    Leppanen, Paavo H T
    Neuhoff, Nina
    Warnke, Andreas
    Schulte-Körne, Gert
    Schumacher, Johannes
    Nöthen, Markus M
    Kere, Juha
    Peyrard-Janvid, Myriam
    SNP variations in the 7q33 region containing DGKI are associated with dyslexia in the Finnish and German populations.2011In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 41, no 1, p. 134-40Article in journal (Refereed)
    Abstract [en]

    Four genes, DYX1C1, ROBO1, DCDC2 and KIAA0319 have been studied both genetically and functionally as candidate genes for developmental dyslexia, a common learning disability in children. The identification of novel genes is crucial to better understand the molecular pathways affected in dyslectic individuals. Here, we report results from a fine-mapping approach involving linkage and association analysis in Finnish and German dyslexic cohorts. We restrict a candidate region to 0.3 Mb on chromosome 7q33. This region harbours the gene diacylglycerol kinase, iota (DGKI) which contains overlapping haplotypes associated with dyslexia in both Finnish and German sample sets.

  • 26. Scerri, Thomas S
    et al.
    Darki, Fahimeh
    Newbury, Dianne F
    Whitehouse, Andrew J O
    Peyrard-Janvid, Myriam
    Matsson, Hans
    Ang, Qi W
    Pennell, Craig E
    Ring, Susan
    Stein, John
    Morris, Andrew P
    Monaco, Anthony P
    Kere, Juha
    Talcott, Joel B
    Klingberg, Torkel
    Paracchini, Silvia
    The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure.2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, article id e50321Article in journal (Refereed)
    Abstract [en]

    Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.

  • 27. Söderqvist, Stina
    et al.
    Bergman Nutley, Sissela
    Peyrard-Janvid, Myriam
    Matsson, Hans
    Humphreys, Keith
    Kere, Juha
    Klingberg, Torkel
    Dopamine, working memory, and training induced plasticity: implications for developmental research.2012In: Developmental Psychology, ISSN 0012-1649, E-ISSN 1939-0599, Vol. 48, no 3, p. 836-43Article in journal (Refereed)
    Abstract [en]

    Cognitive deficits and particularly deficits in working memory (WM) capacity are common features in neuropsychiatric disorders. Understanding the underlying mechanisms through which WM capacity can be improved is therefore of great importance. Several lines of research indicate that dopamine plays an important role not only in WM function but also for improving WM capacity. For example, pharmacological interventions acting on the dopaminergic system, such as methylphenidate, improve WM performance. In addition, behavioral interventions for improving WM performance in the form of intensive computerized training have recently been associated with changes in dopamine receptor density. These two different means of improving WM performance--pharmacological and behavioral--are thus associated with similar biological mechanisms in the brain involving dopaminergic systems. This article reviews some of the evidence for the role of dopamine in WM functioning, in particular concerning the link to WM development and cognitive plasticity. Novel data are presented showing that variation in the dopamine transporter gene (DAT1) influences improvements in WM and fluid intelligence in preschool-age children following cognitive training. Our results emphasize the importance of the role of dopamine in determining cognitive plasticity.

  • 28. Söderqvist, Stina
    et al.
    Matsson, Hans
    Peyrard-Janvid, Myriam
    Kere, Juha
    Klingberg, Torkel
    Polymorphisms in the dopamine receptor 2 gene region influence improvements during working memory training in children and adolescents.2014In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 26, no 1, p. 54-62Article in journal (Refereed)
    Abstract [en]

    Studying the effects of cognitive training can lead to finding better treatments, but it can also be a tool for investigating factors important for brain plasticity and acquisition of cognitive skills. In this study, we investigated how single-nucleotide polymorphisms (SNPs) and ratings of intrinsic motivation were associated to interindividual differences in improvement during working memory training. The study included 256 children aged 7-19 years who were genotyped for 13 SNPs within or near eight candidate genes previously implicated in learning: COMT, SLC6A3 (DAT1), DRD4, DRD2, PPP1R1B (DARPP32), MAOA, LMX1A, and BDNF. Ratings on the intrinsic motivation inventory were also available for 156 of these children. All participants performed at least 20 sessions of working memory training, and performance during the training was logged and used as the outcome variable. We found that two SNPs, rs1800497 and rs2283265, located near and within the dopamine receptor 2 (DRD2) gene, respectively, were significantly associated with improvements during training (p < .003 and p < .0004, respectively). Scores from a questionnaire regarding intrinsic motivation did not correlate with training outcome. However, we observed both the main effect of genotype at those two loci as well as the interaction between genotypes and ratings of intrinsic motivation (perceived competence). Both SNPs have previously been shown to affect DRD2 receptor density primarily in the BG. Our results suggest that genetic variation is accounting for some interindividual differences in how children acquire cognitive skills and that part of this effect is also seen on intrinsic motivation. Moreover, they suggest that dopamine D2 transmission in the BG is a key factor for cognitive plasticity.

  • 29. Söderqvist, Stina
    et al.
    McNab, Fiona
    Peyrard-Janvid, Myriam
    Matsson, Hans
    Humphreys, Keith
    Kere, Juha
    Klingberg, Torkel
    The SNAP25 gene is linked to working memory capacity and maturation of the posterior cingulate cortex during childhood.2010In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 68, no 12, p. 1120-5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Working memory (WM) is the ability to retain task relevant information. This ability is important for a wide range of cognitive tasks, and WM deficits are a central cognitive impairment in neurodevelopment disorders such as attention-deficit/hyperactivity disorder (ADHD). Although WM capacity is known to be highly heritable, most genes involved remain unidentified.

    METHODS: Single nucleotide polymorphisms in genes previously associated with cognitive functions or ADHD were selected for genotyping. Associations of these with WM tasks were investigated in a community sample of 330 children and young adults. One single nucleotide polymorphisms was also investigated in an independent sample of 88 4-year-old children. Furthermore, association between brain structure and activity, as measured by magnetic resonance imaging techniques, and single nucleotide polymorphisms alleles were estimated in 88 participants.

    RESULTS: Genotype at rs363039, located in the gene coding for synaptosomal-associated protein, 25 kDa (SNAP25) was associated to WM capacity in both samples. Associations in the community sample were also found with measures of other cognitive functions. In addition, this polymorphism affected the gray matter and brain activity in the posterior cingulate cortex, an area included in the so-called default mode network previously correlated to regulation of attention and hypothesized to be implicated in ADHD.

    CONCLUSIONS: A novel gene-brain-behavior network was identified in which a genotype located in SNAP25 affects WM and has age-dependent effects on both brain structure and brain activity. Identifying such networks could be a key to better understanding cognitive development as well as some of its disorders.

  • 30. Tammimies, Kristiina
    et al.
    Vitezic, Morana
    Matsson, Hans
    Le Guyader, Sylvie
    Bürglin, Thomas R
    Ohman, Tiina
    Strömblad, Staffan
    Daub, Carsten O
    Nyman, Tuula A
    Kere, Juha
    Tapia-Páez, Isabel
    Molecular networks of DYX1C1 gene show connection to neuronal migration genes and cytoskeletal proteins.2013In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 73, no 6, p. 583-90, article id S0006-3223(12)00722-6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The dyslexia susceptibility 1 candidate 1 (DYX1C1) gene has recently been associated with dyslexia and reading scores in several population samples. The DYX1C1 has also been shown to affect neuronal migration and modulate estrogen receptor signaling.

    METHODS: We have analyzed the molecular networks of DYX1C1 by gene expression and protein interaction profiling in a human neuroblastoma cell line.

    RESULTS: We find that DYX1C1 can modulate the expression of nervous system development and neuronal migration genes such as RELN and associate with a number of cytoskeletal proteins. We also show by live cell imaging that DYX1C1 regulates cell migration of the human neuroblastoma cell line dependent on its tetratricopeptide repeat and DYX1 protein domains. The DYX1 domain is a novel highly conserved domain identified in this study by multiple sequence alignment of DYX1C1 proteins recovered from a wide range of eukaryotic species.

    CONCLUSIONS: Our results contribute to the hypothesis that dyslexia has a developmental neurobiological basis by linking DYX1C1 with many genes involved in neuronal migration disorders.

  • 31. Ziermans, T
    et al.
    Dumontheil, I
    Roggeman, C
    Peyrard-Janvid, M
    Matsson, H
    Kere, J
    Klingberg, T
    Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development.2012In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 2, article id e85Article in journal (Refereed)
    Abstract [en]

    A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene-brain-behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ~6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development.

1 - 31 of 31
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