title: Levetiracetam resistance: Synaptic signatures & corresponding promoter SNPs in epileptic hippocampi.
abstract: Pharmacoresistance to antiepileptic drugs (AEDs) is a major clinical problem in patients with mesial temporal lobe epilepsy (mTLE). Levetiracetam (LEV) represents a unique type of AED as its high-affinity binding site, the synaptic vesicle protein SV2A, is a component of the presynaptic release machinery. LEV often leads to full seizure control even in previously refractory patients. However, approximately 30% of LEV-treated mTLE patients do not show a significant response to LEV from the beginning of the pharmacotherapy and are therefore classified as a priori non-responders. This unexpected phenomenon prompted genetic studies, which failed to characterize responsible SV2A sequence alterations. Here, we followed a different approach to study the mechanisms of LEV pharmacoresistance by screening for mRNA signatures specifically expressed in LEV a priori non-responders in epileptic brain tissue and subsequent promoter analyses of highly altered transcripts. To this end, we have used our unique access to analyze hippocampal tissue from pharmacoresistant TLE patients who underwent epilepsy surgery for seizure control (n = 53) stratified according to a priori LEV responders versus patients with impaired LEV-response. Transcriptome (Illumina platform) and subsequent multimodal cluster analyses uncovered strikingly abundant synapse-associated molecule mRNA signatures in LEV a priori non-responders. Subsequent promoter characterization revealed accumulation of the single nucleotide polymorphism (SNP) rs9305614 G-allele in a priori non-responders to correlate to abundant mRNAs of phosphatidylinositol N-acetylglucosaminyltransferase (PIGP), i.e. a key component of the Wnt-signaling pathway. By luciferase assays, we observed significantly stronger activation by the LBP-1 transcription factor of the rs9305614 G-allele PIGP promoter. The present data suggest an abundance of transcripts encoding for key synaptic components in the hippocampi of LEV a priori non-responder mTLE patients, which for PIGP as proof of concept can be explained by a particular promoter variant. Our data argue for epigenetic factors predisposing for a priori LEV pharmacoresistance by transcriptional 'overexposure of targets'.
authors.affiliation: Dept. of Neuropathology, University of Bonn Medical Center, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Grimminger
authors.forename: Katharina
authors.initials: K
authors.lastname: Pernhorst
authors.forename: Rainer
authors.initials: R
authors.lastname: Surges
authors.forename: Pitt
authors.initials: P
authors.lastname: Niehusmann
authors.forename: Lutz
authors.initials: L
authors.lastname: Priebe
authors.forename: Marec
authors.initials: M
authors.lastname: von Lehe
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Susanne
authors.initials: S
authors.lastname: Schoch
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Becker
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006602:Hexosyltransferases / Q000235:genetics* / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007223:Infant; D000077287:Levetiracetam; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010889:Piracetam / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D017729:Presynaptic Terminals / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D008565:Membrane Proteins; D000077287:Levetiracetam; D006602:Hexosyltransferases; C414441:PIGP protein, human; D010889:Piracetam
keywords: A priori non-responders; Luciferase; PIGP; Presynapse; Promoter variants