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Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1)

Molecular Psychiatry volume 5, pages 275–282 (2000)Cite this article

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.

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References

  1. Uhl GR . Neurotransmitter (plus): a promising gene family Trends Neurosci 1992; 15: 265–268

    Article  CAS  PubMed  Google Scholar 

  2. Amara SG, Kuhar MJ . Neurotransmitter transporters: recent progress Annu Rev Neurosci 1993; 16: 73–93

    Article  CAS  PubMed  Google Scholar 

  3. Giros B, Caron MG . Molecular characterization of the dopamine transporter Trends Pharmacol Sci 1993; 14: 43–49

    Article  CAS  PubMed  Google Scholar 

  4. 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

    Article  CAS  PubMed  Google Scholar 

  5. Ritz MC, Kuhar MJ . Psychostimulant drugs and a dopamine hypothesis regarding addiction: an update on recent research Biochem Soc Symp 1993; 59: 51–64

    CAS  PubMed  Google Scholar 

  6. Kitayama S, Wang J-B, Uhl GR . Dopamine transporter mutants selectively enhance MPP+ transport Synapse 1993; 15: 58–62

    Article  CAS  PubMed  Google Scholar 

  7. Edvardsen O, Dahl SG . A putative model of the dopamine transporter Mol Brain Res 1994; 27: 265–274

    Article  CAS  PubMed  Google Scholar 

  8. 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

    CAS  PubMed  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  10. 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

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. Kawarai T, Kawakami H, Yamamura Y, Nakamura S . Structure and organization of the gene encoding human dopamine transporter Gene 1997; 195: 11–18

    Article  CAS  PubMed  Google Scholar 

  14. 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

    PubMed  PubMed Central  Google Scholar 

  15. 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

    Article  CAS  PubMed  Google Scholar 

  16. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. 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

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. Gelernter J, Kranzler HR, Satel SL, Rao PA . Genetic association between dopamine transporter protein alleles and cocaine-induced paranoia Neuropsychopharmacology 1994; 11: 195–200

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  CAS  PubMed  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. Endicott J, Spitzer RL . A diagnostic interview: the schedule for affective disorders and schizophrenia Arch Gen Psychiatry 1978; 35: 837–844

    Article  CAS  PubMed  Google Scholar 

  25. 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

  26. 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

    Google Scholar 

  27. 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

    Article  CAS  PubMed  Google Scholar 

  28. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells Nucleic Acids Res 1988; 16: 1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Lewontin RC . The interaction of selection and linkage. I. General considerations; heterotic models Genetics 1964; 49: 49–67

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Terwilliger JD, Ott J . Handbook of Human Genetic Linkage Johns Hopkins University Press: Baltimore 1994

    Google Scholar 

  32. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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

    Article  CAS  PubMed  Google Scholar 

  34. Homer JP, Flodman PM, Spence MA . Bipolar disorder: dominant or recessive on chromosome 5? Genet Epidemiol 1997; 14: 647–651

    Article  CAS  PubMed  Google Scholar 

  35. 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

    Article  CAS  PubMed  Google Scholar 

  36. 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

    Article  CAS  PubMed  Google Scholar 

  37. 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

    Article  CAS  PubMed  Google Scholar 

  38. Lee FJS, Pristupa ZB, Ciliax BJ, Levey AI, Niznik HB . The dopamine transporter carboxyl-terminal tail J Biol Chem 1996; 271: 20885–20894

    Article  CAS  PubMed  Google Scholar 

  39. 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

    Article  CAS  PubMed  Google Scholar 

  40. 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

    Article  CAS  PubMed  Google Scholar 

  41. 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

    Article  PubMed  Google Scholar 

  42. 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

    Article  PubMed  Google Scholar 

  43. 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

    Google Scholar 

  44. 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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft (SFB 400 ‘Molekulare Grundlagen zentralnervöser Erkrankungen’, Teilprojekte A3 and D3).

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Authors and Affiliations

  1. Institute of Human Genetics, University of Bonn, Wilhelmstr 31, Bonn, 53111, Germany

    F Grünhage, S Cichon, P Propping & M M Nöthen

  2. Department of Psychiatry, University of Bonn, Sigmund-Freud-Str 25, Bonn, 53105, Germany

    T G Schulze, D J Müller, W Maier & M Rietschel

  3. Department of Psychiatry, University of Würzburg, Füchsleinstr 15, Würzburg, 97080, Germany

    M Lanczik & E Franzek

  4. Mental State Hospital Haar, Vockestr 72, Haar, 85540, Germany

    M Albus & M Borrmann-Hassenbach

  5. Department for Medical Statistics, University of Bonn, Sigmund-Freud-Str 25, Bonn, 53105, Germany

    M Knapp

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  1. F Grünhage
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  2. T G Schulze
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  3. D J Müller
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Correspondence to M M Nöthen.

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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

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  • DOI: https://doi.org/10.1038/sj.mp.4000711

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