title: Gilles de la Tourette syndrome is associated with hypermethylation of the dopamine D2 receptor gene.
abstract: Several lines of evidence support a "dopaminergic hypothesis" in the pathophysiology of Gilles de la Tourette syndrome (TS). The aim of this study was to investigate for the first time epigenetic changes in DNA methylation in different dopamine genes in adult patients with TS. We included 51 well characterized adult patients with TS (41 males, 10 females, mean age = 35 ± 12.6 years, range, 18-71 years) and compared results with data from a group of 51 sex- and age-matched healthy controls. Bisulfite sequencing was used to measure peripheral DNA methylation of the dopamine transporter (DAT), the dopamine D2 receptor (DRD2), and the catechol-O-methyltransferase (COMT) genes. Compared to healthy controls, patients with TS showed significantly elevated methylation level of the DRD2 gene that positively correlated with tic severity. In contrast, DAT methylation was lower in more severely affected patients. Our results provide evidence for a role of altered epigenetic regulation of dopaminergic genes in the pathophysiology of TS. While DRD2 hypermethylation seems to be directly related to the neurobiology of TS that may lead to dopaminergic dysfunction resulting in enhanced thalamo-cortical movement-stimulating activity, DAT hypomethylation might reflect a secondary mechanism in order to compensate for increased dopaminergic signal transduction due to DRD2 hypermethylation. In addition, it can be speculated that spontaneous fluctuations of tics may be caused by short-term alterations of methylation levels of dopaminergic genes resulting in dynamic changes of tonic/phasic dopaminergic signaling in the striatum and thalamo-cortical output pathways.
authors.affiliation: Clinic of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Germany. Electronic address: mueller-vahl.kirsten@mh-hannover.de.
authors.forename: Kirsten R
authors.initials: KR
authors.lastname: Müller-Vahl
authors.affiliation: Clinic of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Germany.
authors.forename: Gesa
authors.initials: G
authors.lastname: Loeber
authors.affiliation: Clinic of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Germany; Molecular Neuroscience Laboratory, Hannover Medical School, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kotsiari
authors.affiliation: Clinic of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Germany; Molecular Neuroscience Laboratory, Hannover Medical School, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Müller-Engling
authors.affiliation: Clinic of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Germany; Molecular Neuroscience Laboratory, Hannover Medical School, Germany.
authors.forename: Helge
authors.initials: H
authors.lastname: Frieling
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D020323:Tics / Q000235:genetics / Q000378:metabolism; D005879:Tourette Syndrome / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C581293:DRD2 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase
keywords: DAT; DRD2; Dopamine; Methylation; Tic; Tourette syndrome