Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations.
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.
Vandenbergh
D J
DJ
Molecular Neurobiology Branch, National Institute on Drug Abuse, NIH, USA.
Thompson
M D
MD
Cook
E H
EH
Bendahhou
E
E
Nguyen
T
T
Krasowski
M D
MD
Zarrabian
D
D
Comings
D
D
Sellers
E M
EM
Tyndale
R F
RF
George
S R
SR
O'Dowd
B F
BF
Uhl
G R
GR
D000293:Adolescent; D000437:Alcoholism / Q000235:genetics*; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D017124:Conserved Sequence; D050483:Dopamine Plasma Membrane Transport Proteins; D005091:Exons; D014644:Genetic Variation; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D018598:Minisatellite Repeats; D009419:Nerve Tissue Proteins; D018807:Polymorphism, Single-Stranded Conformational; D019966:Substance-Related Disorders / Q000235:genetics*; D005879:Tourette Syndrome / Q000235:genetics*
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human