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

D. J VANDENBERGH; M. D THOMPSON; S. R GEORGE; B. F O'DOWD; G. R UHL; E. H COOK; E BENDAHHOU; T NGUYEN; M. D KRASOWSKI; D ZARRABIAN; D COMINGS; E. M SELLERS; R. F TYNDALE

doi:10.1038/sj.mp.4000701

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

Journal article

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

D. J VANDENBERGH, M. D THOMPSON, S. R GEORGE, B. F O'DOWD, G. R UHL, E. H COOK, E BENDAHHOU, T NGUYEN, M. D KRASOWSKI, D ZARRABIAN, …

Molecular psychiatry, Vol.5(3), pp.283-292

2000

DOI: 10.1038/sj.mp.4000701

PMID: 10889531

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Abstract

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.

Biological and medical sciences

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Psychology. Psychoanalysis. Psychiatry

Medical sciences

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Psychopathology. Psychiatry

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Title: Subtitle: Human dopamine transporter gene : coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations
Creators: D. J VANDENBERGH - Molecular Neurobiology Branch, National Institute on Drug Abuse, NIH, Toronto, Ontario M5S 2S1, Canada
M. D THOMPSON - Laboratory of Developmental Neuroscience, Department of Psychiatry, University of Chicago, Chicago, United States
S. R GEORGE - Sunnybrook and Women's College Health Science Centre, University of Toronto, Toronto, Ontario, Canada
B. F O'DOWD - Laboratory of Developmental Neuroscience, Department of Psychiatry, University of Chicago, Chicago, United States
G. R UHL - Molecular Neurobiology Branch, National Institute on Drug Abuse, NIH, Toronto, Ontario M5S 2S1, Canada
E. H COOK - Department of Medical Genetics, City of Hope Medical Center, Duarte, California, United States
E BENDAHHOU - Molecular Neurobiology Branch, National Institute on Drug Abuse, NIH, Toronto, Ontario M5S 2S1, Canada
T NGUYEN - Laboratory of Developmental Neuroscience, Department of Psychiatry, University of Chicago, Chicago, United States
M. D KRASOWSKI - Department of Medical Genetics, City of Hope Medical Center, Duarte, California, United States
D ZARRABIAN - Laboratory of Developmental Neuroscience, Department of Psychiatry, University of Chicago, Chicago, United States
D COMINGS - Centre for Addiction and Mental Health, and Departments of Pharmacology, Psychiatry and Medicine, Toronto, Ontario, Canada
E. M SELLERS - Sunnybrook and Women's College Health Science Centre, University of Toronto, Toronto, Ontario, Canada
R. F TYNDALE - Sunnybrook and Women's College Health Science Centre, University of Toronto, Toronto, Ontario, Canada
Resource Type: Journal article
Publication Details: Molecular psychiatry, Vol.5(3), pp.283-292
DOI: 10.1038/sj.mp.4000701
PMID: 10889531
NLM abbreviation: Mol Psychiatry
ISSN: 1359-4184
eISSN: 1476-5578
Publisher: Nature Publishing Group; Basingstoke
Language: English
Date published: 2000
Academic Unit: Pathology
Record Identifier: 9984047724602771

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