Tourette syndrome and the norepinephrine transporter gene: Results of a systematic mutation screening

Abstract

Tourette syndrome (TS) is a complex inherited neuropsychiatric disorder characterized by multiple motor and phonic tics. Involvement of central norepinephrine mechanisms is suggested by central norepinephrinic hyperactivity in patients with TS and by the therapeutic effects of the presynaptic alpha2-adrenergic agonist clonidine. The norepinephrine transporter gene (NET) was systematically screened by single-strand conformation analysis for genetic variants, including the whole coding region and adjacent exon-intron boundaries in 43 patients with TS and 46 healthy controls. We detected 12 DNA sequence variants, among them four missense mutations (Val69Ile, Thr99Ile, Va1245Ile, and Gly478Ser). The observed missense mutations may alter conformational rearrangements during gating of the transporter, assembly of subunits, and norepinephrine-specific uptake affinity. Allele frequency and genotype distribution of the genetic variants showed no differences between TS patients and controls. No mutation of likely functional significance was found that distinguished TS patients from healthy controls, indicating that genetic variants of the NET gene are not causally related to Tourette syndrome.

A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder

“…Accordingly, genetic variations of SLC6A2 are considered to be promising candidates for NE-related disorders. For instance, several polymorphisms have been identified in the coding regions of SLC6A2 (12,29) including a functional missense mutation (Ala457Pro) that is linked to orthostatic intolerance. In contrast, similar analyses of SLC6A2 variants with various psychiatric disorders, including major depression, Tourette syndrome, bipolar disorder, schizophrenia, and alcoholism have failed to reveal significant association (29).…”

“…For instance, several polymorphisms have been identified in the coding regions of SLC6A2 (12,29) including a functional missense mutation (Ala457Pro) that is linked to orthostatic intolerance. In contrast, similar analyses of SLC6A2 variants with various psychiatric disorders, including major depression, Tourette syndrome, bipolar disorder, schizophrenia, and alcoholism have failed to reveal significant association (29). Studies of the association between SLC6A2 SNPs and ADHD have yielded mixed results, with several studies finding no evidence for association (14,15) and more recent studies providing some evidence for association (16,17).…”

Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1)

“…39,40 We have previously studied the norepinephrine transporter gene in 180 unrelated individuals and found five missense substitutions only one of which had a frequency of Ͼ1%. 41,42 These results suggest that low variability is a general feature of the monoamine transporter family. However, genetic variability is not restricted to the amino acid composition of the protein, it may be present in regulatory regions and thereby alter protein expression.…”

Current issues in Tourette syndrome

“…42 An additional approach has been to search for a linkage to candidate genes, often those associated with specific synaptic markers. Recent linkage studies, however, have yielded no positive results to dopamine D1-5 receptors [43][44][45][46] ; glycine alpha 1 subunit (GLRA1), GABA A receptor alpha-1, alpha-6, and gamma-2 subunits (GABRA1, GABRA6, GABRG2), GABA A receptor beta-1 and alpha-2 subunits (GABARB1, GABARA2), glutamate receptor GLUR1, the alpha adrenergic receptor ADRA1, the beta adrenergic receptor ADRB2, and the glucocorticoid receptor GRL 47 ; norepinephrine transporter gene 48 ; and catecholo-methyltransferase. 49 Investigators have also sought to identify associations between TS and other movement disorders.…”