Identification of susceptibility genes for dyslexia

Abstract: p>Developmental dyslexia, also known as specific reading disability, is characterized by persistent difficulties in learning to read and spell in spite of adequate intelligence, education, social environment, and normal senses. It is the most common learning disability affecting 5-10% of school-aged children. The core deficit in dyslexia is believed to involve phonological processing. Dyslexia has a complex genetic basis, and family studies as well as extensive molecular genetic studies have proven the importance of genetic factors in the development of this disorder. To date, nine chromosomal regions have been identified as susceptibility loci for dyslexia; DYX1 DYX9. DYX1C1 on chromosome 15q21 was the first candidate gene suggested based on the cloning of a translocation breakpoint co-segregating with dyslexia. The aim of this thesis project was to identify susceptibility genes for dyslexia primarily by using a positional cloning approach. Specifically, three candidate loci for dyslexia were studied; DYX1, DYX2, and DYX3. Several rounds of genetic mapping within the DYX3 region lead to the identification of overlapping dyslexia risk haplotypes in two independent sample sets. Carriers of the risk haplotype showed attenuated expression of two co-expressed genes within the region, MRPL19 and C2ORF3, indicating a possible regulatory effect of the risk variants. Linkage disequilibrium mapping within the most replicated susceptibility for dyslexia, DYX2, revealed a strong genetic effect for DCDC2 in dyslexic individuals, in particular in more severely affected cases. The effect of this gene as a susceptibility factor for dyslexia was confirmed by replication analysis in an independent sample set. Replication efforts of DYX1C1 have shown inconsistent results, and thus its role in the development of dyslexia has been considered unsettled. We refined the haplotype structure by analyzing additional variants within the DYX1C1 locus. The haplotypes showed association with dyslexia in a large sample set, with possible sex-specific effects. Refined mapping of another translocation within the DYX1 region co-segregating with dyslexia located the breakpoint to the complex promoter region of CYP19A1 (aromatase). Genetic variation within CYP19A1 associated with speech and language measures and dyslexia in three independent sample sets. Variation in the highly conserved brain promoter of CYP19A1 altered transcription factor binding. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. Brain morphology studies of aromatase-deficient mice showed increased cortical neuronal density and occasional cortical heterotopias, similar to those observed in human dyslexic brains. To date, seven candidate susceptibility genes have been suggested for dyslexia. In addition to the ones studied in this thesis, KIAA0319 within DYX2 and ROBO1 within DYX5 have been indicated in dyslexia. Studies of the dyslexia candidate genes in rats and mice implicate neuronal migration and axon guidance as neurobiological mechanisms that likely mediate this disorder. Anatomical studies support this hypothesis as cortical abnormalities have been observed in dyslexic brains. Functional brain imaging studies show that these disrupted areas are involved in phonological processing and display abnormal activation in dyslexics. Taken together, our results and these studies implicate a biological basis for developmental dyslexia.