Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR

Abstract

An insertion/deletion polymorphism in the SERT linked promoter region (SERTLPR), previously reported to regulate mRNA expression in vitro, has been associated with mental disorders and response to psychotropic drugs. Contradictory evidence, however, has raised questions about the role of SERTLPR in regulating mRNA expression in vivo. We have used analysis of allelic expression imbalance (AEI) of SERT mRNA to assess quantitatively the contribution of SERTLPR to mRNA expression in human post-mortem pons tissue sections containing serotonergic neurons of the dorsal and median raphe nuclei. Any difference in the expression of one allele over the other indicates the presence of cis-acting elements that differentially affect transcription and/or mRNA processing and turnover. Using a marker SNP in the 3 0 untranslated region of SERT mRNA, statistically significant differences in allelic mRNA levels were detected in nine out of 29 samples heterozygous for the marker SNP. While the allelic expression differences were relatively small (15-25%), they could nevertheless be physiologically relevant. Although previous results had suggested that the long form of SERTLPR yields higher mRNA levels than the short form, we did not observe a correlation between SERTLPR and allelic expression ratios. Also in contrast to previous results, we found no correlation between SERTLPR and allelic expression ratios or SERT mRNA levels in Blymphocytes. This study demonstrates that regulation of SERT mRNA is independent of SERTLPR, but could be associated with polymorphisms in partial linkage disequilibrium with SERTLPR.

Enhanced Serotonin Transporter Function during Depression in Seasonal Affective Disorder

“…While the abovedescribed influence of season on 5-HTT turnover rates and maximal 5-HT uptake velocity was confirmed in this analysis, the factor genotype (see also Lim et al, 2006) and the interaction terms genotype  season did not reach significance in any of the analyses (data not shown).…”

Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons

“…The demographics of this collection have been described previously. 15 Oligonucleotide primers were designed using the program Oligo 4.0 (National Biosciences Inc., Plymouth, MN, USA) and synthesized by Integrated DNA Technologies (Coralville, IA, USA).…”

“…15 Briefly, frozen sections of pons were incubated in 10 volumes of RNAlater-ICE Frozen Tissue Transition solution (Ambion Inc., Austin, TX, USA) overnight at À801C to maximize recovery of DNA and RNA. The next day, a small piece of tissue from the ventral edge of each sample was removed and homogenized in DNA lysis buffer for isolation of genomic DNA and the remaining portion of the sample homogenized in Trizol reagent (Invitrogen, Carlsbad, CA, USA) for isolation of total RNA.…”

“…We have previously used this technique to quantify AEI of mRNAs encoding human H þ / dipeptide transporter 2 (PEPT2), 12 p-glycoprotein (MDR1), 13 the m-opiate receptor (OPRM), 14 and the serotonin transporter (SERT). 15 The goal of this study was to determine whether allele-specific mRNA expression of TPH2 gene occurs and, if so, identify cis-acting genetic elements that predict high or low levels of expression.…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…68,[70][71][72][73] However, the translation of in vitro findings into in vivo functioning does not appear straightforward. Human neuroimaging studies of 5-HTT availability [74][75][76][77][78][79] and post-mortem studies of 5-HTT bindings and rRNA expression [80][81][82] have not detected any consistent effect of 5-HTTLPR. No reliable association was found between 5-HTLPR and the level of serotonin metabolite in the cerebrospinal fluid.…”