Tsortouktzidis, Despina, Schulz, Herbert, Hamed, Motaz, Vatter, Hartmut, Surges, Rainer, Schoch, Susanne, Sander, Thomas, Becker, Albert J. and van Loo, Karen M. J. . Gene expression analysis in epileptic hippocampi reveals a promoter haplotype conferring reduced aldehyde dehydrogenase 5a1 expression and responsiveness. Epilepsia. HOBOKEN: WILEY. ISSN 1528-1167

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Abstract

Increasing evidence indicates the pathogenetic relevance of regulatory genomic motifs for variability in the manifestation of brain disorders. In this context, cis-regulatory effects of single nucleotide polymorphisms (SNPs) on gene expression can contribute to changing transcript levels of excitability-relevant molecules and episodic seizure manifestation in epilepsy. Biopsy specimens of patients undergoing epilepsy surgery for seizure relief provide unique insights into the impact of promoter SNPs on corresponding mRNA expression. Here, we have scrutinized whether two linked regulatory SNPs (rs2744575; 4779C > G and rs4646830; 4854C > G) located in the aldehyde dehydrogenase 5a1 (succinic semialdehyde dehydrogenase; ALDH5A1) gene promoter are associated with expression of corresponding mRNAs in epileptic hippocampi (n = 43). The minor ALDH5A1-GG haplotype associates with significantly lower ALDH5A1 transcript abundance. Complementary in vitro analyses in neural cell cultures confirm this difference and further reveal a significantly constricted range for the minor ALDH5A1 haplotype of promoter activity regulation through the key epileptogenesis transcription factor Egr1 (early growth response 1). The present data suggest systematic analyses in human hippocampal tissue as a useful approach to unravel the impact of epilepsy candidate SNPs on associated gene expression. Aberrant ALDH5A1 promoter regulation in functional terms can contribute to impaired gamma-aminobutyric acid homeostasis and thereby network excitability and seizure propensity.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Tsortouktzidis, DespinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulz, HerbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamed, MotazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vatter, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Surges, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoch, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, Albert J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Loo, Karen M. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-308087
DOI: 10.1111/epi.16789
Journal or Publication Title: Epilepsia
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1528-1167
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SUCCINATE SEMIALDEHYDE DEHYDROGENASE; FUNCTIONAL-ANALYSIS; ALDH5A1 GENE; TRANSCRIPTION; VARIANTS; GENOMEMultiple languages
Clinical NeurologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/30808

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