Universität zu Köln

Pernhorst, Katharina, Raabe, Anna, Niehusmann, Pitt, van Loo, Karen M. J., Grote, Alexander, Hoffmann, Per ORCID: 0000-0002-6573-983X, Cichon, Sven ORCID: 0000-0002-9475-086X, Sander, Thomas, Schoch, Susanne and Becker, Albert J. (2011). Promoter Variants Determine gamma-Aminobutyric Acid Homeostasis-Related Gene Transcription in Human Epileptic Hippocampi. J. Neuropathol. Exp. Neurol., 70 (12). S. 1080 - 1089. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 0022-3069

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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; GABA(A) beta 3), both of which are present in the 5' regulatory region of genes involved in F-aminobutyric acid (GABA) homeostasis. To address their 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 extent in 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 in GABRB3 promoters, respectively. Using in vitro luciferase transfection assays, we observed that, in both cases, the transcription factors regulate 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pernhorst, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Raabe, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Niehusmann, Pitt UNSPECIFIED UNSPECIFIED UNSPECIFIED van Loo, Karen M. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grote, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffmann, Per UNSPECIFIED orcid.org/0000-0002-6573-983X UNSPECIFIED Cichon, Sven UNSPECIFIED orcid.org/0000-0002-9475-086X UNSPECIFIED Sander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoch, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Albert J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-484878
DOI:	10.1097/NEN.0b013e318238b9af
Journal or Publication Title:	J. Neuropathol. Exp. Neurol.
Volume:	70
Number:	12
Page Range:	S. 1080 - 1089
Date:	2011
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	0022-3069
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TEMPORAL-LOBE EPILEPSY; IDIOPATHIC GENERALIZED EPILEPSY; SEMIALDEHYDE DEHYDROGENASE; EXPRESSION PATTERNS; SCORING MATRICES; UP-REGULATION; ASSOCIATION; DEPRESSION; SEQUENCES; SOFTWARE Multiple languages Clinical Neurology; Neurosciences; Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48487