4 research outputs found
Identification of susceptibility genes for dyslexia
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
Strong Genetic Evidence of DCDC2 as a Susceptibility Gene for Dyslexia
We searched for linkage disequilibrium (LD) in 137 triads with dyslexia, using markers that span the most-replicated dyslexia susceptibility region on 6p21-p22, and found association between the disease and markers within the VMP/DCDC2/KAAG1 locus. Detailed refinement of the LD region, involving sequencing and genotyping of additional markers, showed significant association within DCDC2 in single-marker and haplotype analyses. The association appeared to be strongest in severely affected patients. In a second step, the study was extended to include an independent sample of 239 triads with dyslexia, in which the association—in particular, with the severe phenotype of dyslexia—was confirmed. Our expression data showed that DCDC2, which contains a doublecortin homology domain that is possibly involved in cortical neuron migration, is expressed in the fetal and adult CNS, which—together with the hypothesized protein function—is in accordance with findings in dyslexic patients with abnormal neuronal migration and maturation