Elevated Expression of SLC6A4 Encoding the Serotonin Transporter (SERT) in Gilles de la Tourette Syndrome.

Mathis Hildonen,Nanette M Debes,Per Guldberg,Victoria A Bjerregaard,Christina Dahl,Amanda M Levy,Zeynep Tümer,Lisbeth Birk Møller

doi:10.3390/genes12010086

Abstract

Gilles de la Tourette syndrome (GTS) is a complex neurodevelopmental disorder characterized by motor and vocal tics. Most of the GTS individuals have comorbid diagnoses, of which obsessive-compulsive disorder (OCD) and attention deficit-hyperactivity disorder (ADHD) are the most common. Several neurotransmitter systems have been implicated in disease pathogenesis, and amongst these, the dopaminergic and the serotonergic pathways are the most widely studied. In this study, we aimed to investigate whether the serotonin transporter (SERT) gene (SLC6A4) was differentially expressed among GTS individuals compared to healthy controls, and whether DNA variants (the SERT-linked polymorphic region 5-HTTLPR, together with the associated rs25531 and rs25532 variants, and the rare Ile425Val variant) or promoter methylation of SLC6A4 were associated with gene expression levels or with the presence of OCD as comorbidity. We observed that SLC6A4 expression is upregulated in GTS individuals compared to controls. Although no specific genotype, allele or haplotype was overrepresented in GTS individuals compared to controls, we observed that the LAC/LAC genotype of the 5-HTTLPR/rs25531/rs25532 three-locus haplotype was associated with higher SLC6A4 mRNA expression levels in GTS individuals, but not in the control group.

Highlights

Gilles de la Tourette syndrome (GTS) is a childhood-onset neurodevelopmental disorder characterized by at least one vocal and multiple motor tics, which begin before age 18 years and persist at least 1 year
As associations between SLC6A4 methylation, expression and gene variants have not been studied in GTS previously, we investigated whether SLC6A4 was differentially expressed in GTS individuals with or without obsessive-compulsive disorder (OCD) compared to healthy controls and assessed whether gene variants or promoter methylation of SLC6A4 were associated with gene expression levels
To investigate whether there was an association between SLC6A4 promoter variants and GTS, we genotyped all the GTS individuals and the controls, and there was no statistically significant difference neither in the genotype distribution (n = 159, p = 0.243) nor in the allele frequencies of the 5-HTTLPR polymorphism (n = 318, p = 0.177) (Table 1)

Summary

Introduction

Gilles de la Tourette syndrome (GTS) is a childhood-onset neurodevelopmental disorder characterized by at least one vocal and multiple motor tics, which begin before age 18 years and persist at least 1 year. Neuroimaging and neurophysiology studies suggest that GTS is associated with altered synaptic neurotransmission systems involving dopamine, serotonin, inhibitory neurotransmitter γ-aminobutyric acid (GABA) and excitatory neurotransmitter glutamate in the cortico-striato-thalamo-cortical circuits [9,10,11]. Candidate gene studies suggest involvement of dopaminergic [12,13,14,15], serotonergic [16,17], glutamatergic [18] and histaminergic [19] pathways in GTS pathogenesis. As early as 1990, Comings reported decreased serotonin/platelet ratio in a large cohort of GTS individuals and family members [22], and a range of drugs with high affinity for serotonin receptors, mainly atypical antipsychotics, have been used to relieve tics [23]. The serotonin system may be involved in GTS pathology directly and/or indirectly through regulation of other neurotransmitter systems, especially the dopaminergic system

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