Abstract
The serotonin transporter, called SLC6A4, SERT or 5-HTT, modulates neurotransmission by removal of serotonin from the synapse of serotonergic neurons, facilitating serotonin reuptake into the presynaptic terminus. Selective serotonin reuptake inhibitors block the action of the serotonin transporter and are used to treat depression and other neuropsychiatric disorders. Three polymorphisms in the 5-HTT gene have been implicated in treatment response and neuropsychiatric disorders. A 44-bp promoter ins/del polymorphism (5-HTTLPR) produces primarily long and/or short alleles due to either 14 (short) or 16 (long) repeats of variably conserved 20–23 bp units. Also implicated, a 17–18 bp variable number tandem repeat found in intron2 (StIn2) is expressed as triallelic content with 9, 10, or 12 repeats (StIn2.9, StIn2.10 or StIn2.12). Finally, a single nucleotide polymorphism rs25531 located within the promoter polymorphic-linked region alters the function of the long promoter allele. We developed a PCR-based fragment analysis assay, which is analyzed on an ABI sequencer, whereby we are able to detect all three genotypes simultaneously. Using this technique, we identified novel sequences, which demonstrate promoter repeat regions containing (1) a 17 repeat with rs25531 A/G polymorphism, (2) two with 18-repeat units, (3) one with 20-repeat units and (4) a 24-repeat sequence. The novel repeats were confirmed by direct sequencing of gel-purified amplicons.
Highlights
The serotonin transporter in the brain is the principal site of action for many antidepressant medications in treating major depressive disorders
The finding that rs25531 is associated with selective serotonin reuptake inhibitor response demand that both 5-HTTLPR and rs25531 be viewed as two independent loci for genotyping, and demonstrate a need for more comprehensive genotyping procedures.[10]
The software was set to allow a variation of ±3 for the promoter polymorphisms and ±3 for the StIn2
Summary
The serotonin transporter in the brain is the principal site of action for many antidepressant medications in treating major depressive disorders. The LA allele was associated with higher 5-HTT-binding potential, an index for 5-HTT density in putamen using 3-(11) C-amino-4-(2-dimethylaminomethylphenyl-sulfanyl) benzonitrile ([11C]DASB) positron emission tomography.[9] The G substitution is observed in the context of S allele (SG), which is very rare and was designated as 14-B and 14-D by Nakamura.[5] The finding that rs25531 is associated with selective serotonin reuptake inhibitor response demand that both 5-HTTLPR and rs25531 be viewed as two independent loci for genotyping, and demonstrate a need for more comprehensive genotyping procedures.[10]
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