Human Molecular Genetics Advance Access originally published online on February 19, 2007
Human Molecular Genetics 2007 16(6):667-677; doi:10.1093/hmg/ddm009
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A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia
1 Department of Biosciences and Nutrition and 2 Department of Clinical Research Center, Karolinska Institutet, 14157 Huddinge, Sweden, 3 Max Planck Institute of Psychiatry, 80804 Munich, Germany, 4 Institute of Human Genetics and 5 Department of Genomics, Life and Brain Center, University of Bonn, 53127 Bonn, Germany, 6 Department of Medical Genetics and 7 Department of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland, 8 Department of Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, 97080 Würzburg, Germany, 9 Department of Pediatric Neurology, Jorvi Hospital, 02740 Espoo, Finland, 10 Department of Psychology, University of Jyväskylä, 40014 Jyväskylä, Finland and 11 Department of Child and Adolescent Psychiatry and Psychotherapy, University of Marburg, 35039 Marburg, Germany
* To whom correspondence should be addressed. Tel: +46 86089158; Fax: +46 87745538; Email: juha.kere{at}biosci.ki.se
Received December 7, 2006; Accepted February 2, 2007
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.
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