Testverfah - Bundesverband Legasthenie und Dyskalkulie eV

15. Kongress des Bundesverbandes Legasthenie Abstractband
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 to 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 dyslexia patients with abnormal neuronal migration
and maturation.
Korrespondenzautor:
Markus M. Nöthen
markus.noethen@uni-bonn.de
++49 0228 6885404
++49 0228 6885401
Dyslexia susceptibility genes on chromosome 6
*Silvia Paracchini
University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, Großbritannien
Dyslexia is one of the most prevalent childhood cognitive disorders and is caused
in large part by genetic factors. Linkage studies have identified several regions that
may contain quantitative trait loci (QTL) for this disorder. The most consistently replicated
linkage is on 6p21.3-23, which has been found in five independent samples,
including our own. By using association analysis we have recently identified a haplotype
on chromosome 6p22 which is associated to dyslexia in two large set of families
(Francks et al., 2004). The haplotype spans a 77 kb region of strong inter-marker
linkage disequilibrium, encompassing the first four exons of KIAA0319, the entire
TTRAP gene and the first exon of THEM2. Mutation screening by DHPLC of all
exons and predicted promoters did not detect obvious functional variants that would
disrupt any of the three genes. The risk haplotype might influence gene transcription
regulation. To test this hypothesis we used the MassARRAY (Sequenom) platform
to determine quantitatively relative differences in allele-specific transcription. We
carried out quantitative analysis in cell lines heterozygous for the risk haplotype
using markers either within the transcript sequences or in proximity of the promoters.
In the second case we took advantage of the recently developed haploChip assay
(Knight et al., 2003). Our data shows that the risk haplotype is association with a
reduction of about 40% of the expression of the KIAA0319 gene. Functional studies
are now underway to understand the biological role of this gene.
Korrespondenzautor:
Silvia Paracchini
silviap@well.ox.ac.uk
++44 1865 287501
73