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

• Published in: Molecular psychiatry Vol. 5; no. 3; pp. 283 - 292
• Main Authors: VANDENBERGH, D. J, THOMPSON, M. D, GEORGE, S. R, O'DOWD, B. F, UHL, G. R, COOK, E. H, BENDAHHOU, E, NGUYEN, T, KRASOWSKI, M. D, ZARRABIAN, D, COMINGS, D, SELLERS, E. M, TYNDALE, R. F
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-05-2000
• Subjects: Adolescent; Alcohol; Alcoholism - genetics; Amino acid sequence; Attention Deficit Disorder with Hyperactivity - genetics; Attention deficit hyperactivity disorder; Base Sequence; Biological and medical sciences; Carrier Proteins - genetics; Child; Cloning; Cocaine; Conserved Sequence; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine receptors; Dopamine transporter; Drug abuse; Drug dependence; Ethanol; Evolutionary conservation; Exons; Gene polymorphism; Genetic Variation; Gilles de la Tourette syndrome; Humans; Hyperactivity; Introns; Linkage Disequilibrium; Medical sciences; Membrane Glycoproteins; Membrane Transport Proteins; Mental disorders; Minisatellite Repeats; Miscellaneous; Nerve Tissue Proteins; Neurobiology; Neurosciences; Neurotransmission; Non-coding RNA; Nucleotide sequence; Parkinson's disease; Polymorphism; Polymorphism, Single-Stranded Conformational; Proteins; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Schizophrenia; Substance-Related Disorders - genetics; Tourette Syndrome - genetics; Treatments; Canada; Chicago Illinois; Toronto Ontario Canada; United States > US; Nervous system diseases; Dopamine; Nucleotide sequence; Hyperactivity; Alcoholism; Genetic determinism; Cerebral disorder; Attentional disorder; Gene; Etiology; Central nervous system disease; Gilles de la Tourette syndrome; Degenerative disease; Mutation; Carrier protein
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4000701

The dopamine transporter (DAT) provides major regulation of the synaptic levels of dopamine and is a principal target of psychostimulant drugs. Associations between DAT gene polymorphisms and human disorders with possible links to dopaminergic neurotransmission, including attention-deficit/hyperactivity disorder (ADHD) and consequences of cocaine and alcohol administration, have been reported. We now report approximately 60000 bp of genomic sequence containing the entire DAT gene. This sequence was used to amplify each of the 15 DAT gene exons and several introns and analyze these amplification products by single-stranded sequence conformation (SSCP) and/or direct sequencing. These results define silent allelic single nucleotide sequence variants in DAT gene exons 2, 6, 9 and 15. Rare conservative mutations are identified in amino acids encoded by DAT exons 2 and 8. Analyses of the common nucleotide variants and the previously reported VNTR in the non-coding region of exon 15 define the pattern of linkage disequilibrium across the DAT 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 criteria for Tourette's syndrome, 64 individuals with DSM-IV diagnoses of ethanol dependence, or 15 individuals with ADHD. These data are consistent with substantial evolutionary conservation of the DAT protein sequence. They suggest that gene variants that alter levels of DAT expression provide the best current candidate mechanism for reported associations between DAT gene markers, ADHD and other more tentatively associated neuropsychiatric disorders.