A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo

Abstract

Polymorphic regions consisting of a variable number of tandem repeats within intron 2 of the gene coding for the serotonin transporter protein 5-HTT have been associated with susceptibility to affective disorders. We have cloned two of these intronic polymorphisms, Stin2.10 and Stin2.12, into an expression vector containing a heterologous minimal promoter and the bacterial LacZ reporter gene. These constructs were then used to produce transgenic mice. In embryonic day 10.5 embryos, both Stin2.10 and Stin2.12 produced consistent ␤-galactosidase expression in the embryonic midbrain, hindbrain, and spinal cord floor plate. However, we observed that the levels of ␤-galactosidase expression produced by both the Stin2.10 and Stin2.12 within the rostral hindbrain differed significantly at embryonic day 10.5. Our data suggest that these polymorphic variable number of tandem repeats regions act as transcriptional regulators and have alleledependent differential enhancer-like properties within an area of the hindbrain where the 5-HTT gene is known to be transcribed at this stage of development.transcriptional regulation ͉ promoter ͉ transgenic mice ͉ LacZ gene ͉ rostral hindbrain

Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

“…We did not observe an association between whole blood 5-HT level, K d , or B max of 5-HTT (measured with [ 3 H]-paroxetine and [ 3 H]-imipramine) and two polymorphismsin the 5-HTT gene, a 5-HTTLPR in the promoter region and a VNTRin intron 2, which act in vitro as transcriptional regulators (Lesch et al, 1996;McKenzie and Quinn, 1999). The lack of association between 5-HT levels and 5-HTT polymorphisms is in accordance with previous reports in individuals suffering from autism (Betancur et al, 2002), alcoholism (Stoltenberg et al, 2002), or in healthy subjects (Greenberg et al, 1998).…”

Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project

“…33 In addition, STin4 was in weak linkage disequilibrium with STin2, which has been associated with enhanced transcription of SLC6A4. 34 The inclusion of interaction terms for SLE, SLC6A4, STin4 and SLEs together explained a further 1.5% of the variance in outcome to escitalopram. This was over and above the 15% explained by baseline depression severity, randomization status, age, sex and the main effects of SLEs and genotype.…”

Evidence of association of serotonin transporter gene polymorphisms with schizophrenia in a South Indian population

“…Functionally, the alleles of STin2 VNTR (STin2.10 and STin2.12) can act as transcriptional regulatory elements, with STin2.12 having a superior enhancer-like property within the developing rostral hindbrain, which may lead to aberrant serotonergic neuron development. 32,33 In spite of the evidence for functional effects of alleles at STin2 VNTR, it is not possible to determine whether this VNTR is causally associated with increased risk of schizophrenia. It has been suggested that individual polymorphisms have a weak influence when compared with the combined effect of 5-HTTLPR and STin2 VNTR polymorphisms on SLC6A4 expression.…”