title: A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia.
abstract: 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.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Heidi
authors.initials: H
authors.lastname: Anthoni
authors.forename: Marco
authors.initials: M
authors.lastname: Zucchelli
authors.forename: Hans
authors.initials: H
authors.lastname: Matsson
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Fransson
authors.forename: Johannes
authors.initials: J
authors.lastname: Schumacher
authors.forename: Satu
authors.initials: S
authors.lastname: Massinen
authors.forename: Päivi
authors.initials: P
authors.lastname: Onkamo
authors.forename: Andreas
authors.initials: A
authors.lastname: Warnke
authors.forename: Heide
authors.initials: H
authors.lastname: Griesemann
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Jaana
authors.initials: J
authors.lastname: Nopola-Hemmi
authors.forename: Heikki
authors.initials: H
authors.lastname: Lyytinen
authors.forename: Gerd
authors.initials: G
authors.lastname: Schulte-Körne
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Myriam
authors.initials: M
authors.lastname: Peyrard-Janvid
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D004410:Dyslexia / Q000235:genetics*; D019143:Evolution, Molecular; D005190:Family; D005260:Female; D005387:Finland; D005858:Germany; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D012269:Ribosomal Proteins / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C072278:GCFC2 protein, human; C496590:MRPL19 protein, human; D024101:Mitochondrial Proteins; D012097:Repressor Proteins; D012269:Ribosomal Proteins