Abstract
The dopamine transporter (DAT) plays a central role in dopaminergic neurotransmission in the human brain. Genetic association studies have used a variable number of tandem repeat (VNTR) polymorphism in the 3′-flanking region of the dopamine transporter gene (DAT1) to implicate the DAT in the development of various neuropsychiatric disorders. In this study, we have examined the possibility that a mutation exists in the coding region of the DAT1 gene which through linkage disequilibrium accounts for the observed associations. The complete coding region, as well as exon–intron boundaries, was screened in 91 unrelated individuals including 45 patients with bipolar affective disorder and 46 healthy control individuals by the means of single strand conformation analysis. Our findings suggest that the DAT1 gene is highly conserved since we detected only two rare missense substitutions (Ala559Val, Glu602Gly) and three silent mutations (242C/T, 1342A/G, and 1859C/T) in the whole coding region. Five sequence variants were observed in intronic sequences but none affects known splice sites. The lack of frequent variants of possible functional relevance indicates that genetic variation in the coding region of the DAT1 gene is not responsible for the previously observed associations with neuropsychiatric disorders. The two rare missense substitutions were found in single bipolar patients but not in controls. Investigation of the patients’ families revealed independent segregation between the Ala559Val variant and affective disorder. The Glu602Gly variant was inherited by the proband from an affected father. It therefore remains possible that Glu602Gly may be a rare cause of bipolar affective disorder.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Uhl GR . Neurotransmitter (plus): a promising gene family Trends Neurosci 1992; 15: 265–268
Amara SG, Kuhar MJ . Neurotransmitter transporters: recent progress Annu Rev Neurosci 1993; 16: 73–93
Giros B, Caron MG . Molecular characterization of the dopamine transporter Trends Pharmacol Sci 1993; 14: 43–49
Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ . Cocaine receptors on dopamine transporters are related to self-administration of cocaine Science 1987; 237: 1219–1223
Ritz MC, Kuhar MJ . Psychostimulant drugs and a dopamine hypothesis regarding addiction: an update on recent research Biochem Soc Symp 1993; 59: 51–64
Kitayama S, Wang J-B, Uhl GR . Dopamine transporter mutants selectively enhance MPP+ transport Synapse 1993; 15: 58–62
Edvardsen O, Dahl SG . A putative model of the dopamine transporter Mol Brain Res 1994; 27: 265–274
Giros B, El Mestikawy S, Godinot N, Zheng K, Han H, Yang-Feng T et al. Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter Mol Pharmacol 1992; 42: 383–390
Vandenbergh DJ, Persico AM, Hawkins AL, Griffin CA, Li X, Wang Jabs E et al. Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR Genomics 1992; 14: 1104–1106
Vandenbergh DJ, Persico AM, Uhl GR . A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element, and provides racially dimorphic TaqI RFLPs Mol Brain Res 1992; 15: 161–166
Byerley W, Hoff M, Holik J, Caron MG, Giros BG . VNTR polymorphism for the human dopamine transporter gene (DAT1) Hum Mol Genet 1993; 2: 335
Sano A, Kondoh K, Kakimoto Y, Kondo I . A 40-nucleotide repeat polymorphism in the human dopamine transporter gene Hum Genet 1993; 91: 405–406
Kawarai T, Kawakami H, Yamamura Y, Nakamura S . Structure and organization of the gene encoding human dopamine transporter Gene 1997; 195: 11–18
Cook EH Jr, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE et al. Association of attention-deficit disorder and the dopamine transporter gene Am J Hum Genet 1995; 56: 993–998
Gill M, Daly G, Heron S, Hawi Z, Fitzgerald M . Confirmation of association between attention deficit hyperactivity disorder and dopamine transporter polymorphism Mol Psychiatry 1997; 2: 311–313
Waldman ID, Rowe DC, Abramowitz A, Kozel ST, Mohr JH, Sherman SL et al. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtypes and severity Am J Hum Genet 1998; 63: 1767–1776
Daly G, Hawi Z, Fitzgerald M, Gill M . Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children Mol Psychiatry 1999; 4: 192–196
Waldman ID, Robinson BF, Feigon SA . Linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder: extending the transmission disequilibrium test (TDT) to examine genetic heterogeneity Genet Epidemiol 1997; 14: 699–704
Blum K, Braverman ER, Wu S, Cull JG, Chen TJ, Gill J et al. Association of polymorphisms of dopamine D2 receptor (DRD2), and dopamine transporter (DAT1) genes with schizoid/avoidant behaviors (SAB) Mol Psychiatry 1997; 2: 239–246
Gelernter J, Kranzler HR, Satel SL, Rao PA . Genetic association between dopamine transporter protein alleles and cocaine-induced paranoia Neuropsychopharmacology 1994; 11: 195–200
Sander T, Harms H, Podschus J, Finckh U, Nickel B, Rolfs A et al. Allelic association of a dopamine transporter gene polymorphism in alcohol dependence with withdrawal seizures or delirium Biol Psychiatry 1997; 41: 299–304
Schmidt LG, Harms H, Kuhn S, Rommelspacher H, Sander T . Modification of alcohol withdrawal by the A9 allele of the dopamine transporter gene Am J Psychiatry 1998; 155: 474–478
Gelernter J, Kranzler H, Lacobelle J . Population studies of polymorphisms at loci of neuropsychiatric interest (tryptophan hydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), μ opioid receptor (OPRM1), and ciliary neurotrophic factor (CNTF)) Genomics 1998; 52: 289–297
Endicott J, Spitzer RL . A diagnostic interview: the schedule for affective disorders and schizophrenia Arch Gen Psychiatry 1978; 35: 837–844
American Psychiatric Association, Committee on Nomenclature and Statistics. Diagnostic and Statistical Manual of Mental Disorders, 3rd edn revised American Psychiatric Association Press: Washington DC 1987
Mannuzza S, Fyer AJ, Endicott J, Klein DF . Family Informant Schedule and Criteria (FISC) Anxiety Disorders Clinic, New York State Psychiatric Institute: New York 1985
Donovan DM, Vandenbergh DJ, Perry MP, Bird GS, Ingersoll R, Nanthakumar E et al. GR. Human and mouse dopamine transporter genes: conservation of 5′-flanking sequence elements and gene structures Mol Brain Res 1995; 30: 327–335
Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells Nucleic Acids Res 1988; 16: 1215
Budowle B, Chakraborty R, Giusti AM, Eisenberg AJ, Allen RC . Analysis of the VNTR locus D1S80 by the PCR followed by high resolution PAGE Am J Hum Genet 1991; 48: 137–144
Lewontin RC . The interaction of selection and linkage. I. General considerations; heterotic models Genetics 1964; 49: 49–67
Terwilliger JD, Ott J . Handbook of Human Genetic Linkage Johns Hopkins University Press: Baltimore 1994
Shapiro M, Senapathy P . RNA splice junctions of different classes of eukaryotes: sequence statistics and fundamental implications in gene expression Nucleic Acids Res 1987; 15: 7155–7174
Kelsoe JR, Dessa Sadovnick A, Kristbjarnarson H, Bergesch P, Mroczkowski-Parker Z, Drennan M et al. Possible locus for bipolar disorder near the dopamine transporter on chromosome 5 Am J Med Genet 1996; 67: 533–540
Homer JP, Flodman PM, Spence MA . Bipolar disorder: dominant or recessive on chromosome 5? Genet Epidemiol 1997; 14: 647–651
Souery D, Lipp O, Mahieu B, Mendelbaum K, De Martelaer V, Van Broeckhoven C et al. Association study of bipolar disorder with candidate genes involved in catecholamine neurotransmission: DRD2, DRD3, DAT1, and TH genes Am J Med Genet 1996; 67: 551–555
Gomez-Casero E, Perez de Castro I, Saiz-Ruiz J, Llinares C, Fernandez-Piqueras J . No association between particular DRD3 and DAT gene polymorphisms and manic-depressive illness in a Spanish sample Psychiatr Genet 1996; 6: 209–212
Manki H, Kanba S, Muramatsu T, Higuchi S, Suzuki E, Matsushita S et al. Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders J Affect Disord 1996; 40: 7–13
Lee FJS, Pristupa ZB, Ciliax BJ, Levey AI, Niznik HB . The dopamine transporter carboxyl-terminal tail J Biol Chem 1996; 271: 20885–20894
Lesch KP, Gross J, Franzek E, Wolozin BL, Riederer P, Murphy DL . Primary structure of the serotonin transporter in unipolar depression and bipolar disorder Biol Psychiatry 1995; 37: 215–223
Di Bella D, Catalano M, Balling U, Smeraldi E, Lesch KP . Systematic screening for mutations in the coding region of the human serotonin transporter (5-HTT) gene using PCR and DGGE Am J Med Genet 1996; 67: 541–545
Stöber G, Nöthen MM, Pörzgen P, Brüss M, Bönisch H, Knapp M et al. Systematic search for variation in the human norepinephrine transporter gene: identification of five naturally occurring missense mutations and study of association with major psychiatric disorders Am J Med Genet 1996; 67: 523–532
Stöber G, Hebebrand J, Cichon S, Brüss M, Bönisch H, Lehmkuhl G et al. Tourette syndrome and the norepinephrine transporter gene: results of a systematic mutation screening Am J Med Genet 1999; 88: 158–163
Heils A, Teufel A, Petri S, Stöber G, Bengel B, Lesch KP . Allelic variation of human serotonin transporter gene expression J Neurochem 1996; 6: 2612–2624
Kouzmenko AP, Pereira AM, Singh BS . Intronic sequences are involved in neural targeting of human dopamine transporter gene expression Biochem Biophys Res Commun 1997; 240: 807–811
Acknowledgements
This study was supported by the Deutsche Forschungsgemeinschaft (SFB 400 ‘Molekulare Grundlagen zentralnervöser Erkrankungen’, Teilprojekte A3 and D3).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Grünhage, F., Schulze, T., Müller, D. et al. Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1). Mol Psychiatry 5, 275–282 (2000). https://doi.org/10.1038/sj.mp.4000711
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4000711
Keywords
This article is cited by
-
Behaviorally penetrant, anomalous dopamine efflux exposes sex and circuit dependent regulation of dopamine transporters
Molecular Psychiatry (2022)
-
The dopamine transporter gene SLC6A3: multidisease risks
Molecular Psychiatry (2022)
-
Dopaminergic Ric GTPase activity impacts amphetamine sensitivity and sleep quality in a dopamine transporter-dependent manner in Drosophila melanogaster
Molecular Psychiatry (2021)
-
Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice
Neuropsychopharmacology (2019)
-
Dopamine and addiction: what have we learned from 40 years of research
Journal of Neural Transmission (2019)