Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivitydisorder populations

The dopamine transporter (DAT) provides major regulation of the synaptic le vels of dopamine and is a principal target of psychostimulant drugs. Associ ations between DAT gene polymorphisms and human disorders with possible lin ks to dopaminergic neurotransmission, including attention-deficit/hyperacti vity disorder (ADHD) and consequences of cocaine and alcohol administration , have been reported. We now report approximately 60 000 bp of genomic sequ ence containing the entire DAT gene. This sequence was used to amplify each of the 15 DAT gene exons and several introns and analyze these amplificati on products by single-stranded sequence conformation (SSCP) and/or direct s equencing. These results define silent allelic single nucleotide sequence v ariants in DAT gene exons 2, 6, 9 and 15. Rare conservative mutations are i dentified in amino acids encoded by DAT exons 2 and 8, Analyses of the comm on nucleotide variants and the previously reported VNTR in the non-coding r egion of exon 15 define the pattern of linkage disequilibrium across the DA T locus. These comprehensive analyses, however, fail to identify any common protein coding DAT sequence variant in more than 150 unrelated individuals free of neuropsychiatric disease, 109 individuals meeting City of Hope cri teria for Tourette's syndrome, 64 individuals with DSM-IV diagnoses of etha nol dependence, or 15 individuals with ADHD. These data are consistent with substantial evolutionary conservation of the DAT protein sequence. They su ggest that gene variants that alter levels of DAT expression provide the be st current candidate mechanism for reported associations between DAT gene m arkers, ADHD and other more tentatively associated neuropsychiatric disorde rs.