Human Molecular Genetics Advance Access published online on July 11, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl174
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1 Division of Biochemistry and Molecular Biology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria; Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria
* To whom correspondence should be addressed. Childhood absence epilepsy (CAE) is considered to exhibit a complex non-mendelian pattern of inheritance. So far, only few CAE susceptibility genes have been identified. In a previous study of our group, an association between the GABAA receptor beta3 subunit (GABRB3) gene and CAE was shown. To further investigate this association we screened 45 CAE patients of the first study for mutations in the 10 exons, the exon/intron boundaries and the regulatory sequences of GABRB3. Although we found no functionally relevant mutation, we did identify 13 SNPs in the GABRB3 gene region from the exon 1a promoter to the beginning of intron 3. Using these SNPs we defined 4 haplotypes for the respective GABRB3 gene region. A transmission disequilibrium test (TDT) in the same 45 CAE patients and their parents indicated a significant association of this region and CAE (p = 0.007075). Reporter gene assays in NT2 cells using exon 1a promoter constructs indicated that the disease associated haplotype 2 promoter causes a significantly lower transcriptional activity than the haplotype 1 promoter that is over-represented in the controls. In silico analysis suggested that an exchange from T (haplotype 1) to C (haplotype 2) within this promoter impairs binding of the neuron specific transcriptional activator N-Oct-3. Electrophoretic mobility shift assays demonstrated that the respective polymorphism reduces the nuclear protein binding affinity, thus explaining the results of the reporter gene assays. Reduced expression of the GABRB3 gene could therefore be one potential cause for the development of CAE, pathogenetically relevant in our patient group.
Received April 10, 2006
Revised June 22, 2006
Accepted July 6, 2006
Article
A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity
Lydia Urak 1,
Martha Feucht 2,
Nahid Fathi 3,
Kurt Hornik 4,
and
Karoline Fuchs 5 *
2 Department of Child and Adolescent Neuropsychiatry, Medical University of Vienna, 1090 Vienna, Austria
3 Division of Biochemistry and Molecular Biology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria
4 Department of Statistics and Mathematics, Vienna University of Economics and Business Administration, 1090 Vienna, Austria
5 Division of Biochemistry and Molecular Biology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria; Section of Biochemical Psychiatry, University Clinic for Psychiatry, Medical University of Vienna, 1090 Vienna, Austria
Karoline Fuchs, E-mail: karoline.fuchs{at}meduniwien.ac.at
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