Promoter Variants Determine γ-Aminobutyric Acid Homeostasis-Related Gene Transcription in Human Epileptic Hippocampi

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Abstract

The functional consequences of single nucleotide polymorphisms associated with episodic brain disorders such as epilepsy and depression are unclear. Allelic associations with generalized epilepsies have been reported for single nucleotide polymorphisms rs1883415 (ALDH5A1; succinic semialdehyde dehydrogenase) and rs4906902 (GABRB3; GABAA β3), both of which are present in the 5′ regulatory region of genes involved in γ-aminobutyric acid (GABA) homeostasis. To addresstheir allelic association with episodic brain disorders and allele-specific impact on the transcriptional regulation of these genes in human brain tissue, DNA and messenger RNA (mRNA) isolated from hippocampi were obtained at epilepsy surgery of 146 pharmacoresistant mesial temporal lobe epilepsy (mTLE) patients and from 651 healthy controls. We found that the C allele of rs1883415 is accumulated to a greater extentin mTLE versus controls. By real-time quantitative reverse transcription–polymerase chain reaction analyses, individuals homozygous for the C allele showed higher ALDH5A1 mRNA expression. The rs4906902 G allele of the GABRB3 gene was overrepresented in mTLE patients with depression; individuals homozygous for the G allele showed reduced GABRB3 mRNA expression. Bioinformatic analyses suggest that rs1883415 and rs4906902 alter the DNA binding affinity of the transcription factors Egr-3 in ALDH5A1 and MEF-2 inGABRB3 promoters, respectively. Using in vitro luciferase transfection assays, we observed that, in both cases, the transcription factorsregulate gene expression depending on the allelic variant in the same direction as in the human hippocampi. Our data suggest that distinct promoter variants may sensitize individuals for differential, potentially stimulus-induced alterations of GABA homeostasis-relevant gene expression. This might contribute to the episodic onset of symptoms and point to new targets for pharmacotherapies.

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