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

Tourette syndrome (TS) is a complex inherited neuropsychiatric disorder cha racterized by multiple motor and phonic ties, Involvement of central norepi nephrine mechanisms is suggested by central norepinephrinic hyperactivity i n patients with TB and by the therapeutic effects of the presynaptic alpha( 2)-adrenergic agonist clonidine, The norepinephrine transporter gene (NET) was systematically screened by single-strand conformation analysis for gene tic variants, including the whole coding region and adjacent exon-intron bo undaries in 43 patients with TS and 46 healthy controls. We detected 12 DNA sequence variants, among them four missense mutations (Va169Ile, Thr99Ile, Val245Ile, and Gly478Ser). The observed missense mutations may alter confo rmational rearrangements during gating of the transporter, assembly of subu nits, and norepinephrine-specific uptake affinity, Allele frequency and gen otype distribution of the genetic variants showed no differences between TS patients and controls. No mutation of likely functional significance was f ound that distinguished TS patients from healthy controls, indicating that genetic variants of the NET gene are not causally related to Tourette syndr ome. (C) 1999 Wiley-Liss, Inc.