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 ␣ 2 -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, Val245Ile, 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. Am.