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Single nucleotide polymorphisms distinguish multiple dopamine transporter alleles in primates: implications for association with attention deficit hyperactivity disorder and other neuropsychiatric disorders

Molecular Psychiatry volume 6, pages 50–58 (2001)Cite this article

Abstract

the human dopamine transporter (dat) gene contains a variable number tandem repeat (vntr; 40 bases/3 to >11 repeats) in the 3′-untranslated region (3′-UTR), resulting in multiple alleles categorized by length. The 10-copy allele has been associated with attention deficit hyperactivity disorder (ADHD), yet it accounts for only a small proportion of symptom variance. We investigated whether the rhesus monkey DAT gene contains a repeat sequence similar to the human and whether this region differs in the five most hyperactive and the five most sedate animals selected from a behaviorally characterized cohort (n = 22). A fixed number tandem repeat (FNTR; 39 bases/12 repeats) was observed in all animals. Accordingly, this FNTR is unbefitting an association of DAT transcript length with hyperactivity. However, sequence analysis revealed potential single nucleotide polymorphisms (SNPs), one of which affects a Bst1107I restriction site. We screened the entire cohort, confirmed that all the rhesus monkeys had repeat regions of the same length, and demonstrated that digestion with Bst1107I was sufficient to distinguish two distinct FNTR alleles. Bst1107I genotype was suggestive but not predictive of hyperactive behavior. Based on these data, we speculated that SNPs may exist in human DAT VNTR alleles. To support this hypothesis, we cloned a portion of a novel 10-repeat allele from the human gene containing an SNP that abolishes a DraI restriction site. We conclude that SNPs create a diversity of DAT alleles between individuals that may be greater than previously identified based solely on the length of the VNTR region, and that alleles of specific sequence may contribute to dopamine-related disorders.

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Acknowledgements

The authors thank Dina Yang for excellent technical assistance and Sandra Talbot for preparation of the manuscript and figures. Supported by DA 06303, DA 11558, DA 00304, MH14275 (BKM), DA 05857 (RD) and RR 00168.

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  1. R De La Garza II

    Present address: Department of Psychiatry, Albert Einstein College of Medicine, Forcheimer 111, 1300 Morris Park Avenue, Bronx, 10461, NY, USA

Authors and Affiliations

  1. Division of Neurochemistry, Harvard Medical School, New England Regional Primate Research Center, One Pine Hill Drive, Southborough, 01772–9102, MA, USA

    G M Miller, R De La Garza II, M A Novak & B K Madras

  2. Dept of Psychology, University of Massachusetts at Amherst, Amherst, 01003, MA, USA

    M A Novak

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Correspondence to B K Madras.

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Miller, G., De La Garza, R., Novak, M. et al. Single nucleotide polymorphisms distinguish multiple dopamine transporter alleles in primates: implications for association with attention deficit hyperactivity disorder and other neuropsychiatric disorders. Mol Psychiatry 6, 50–58 (2001). https://doi.org/10.1038/sj.mp.4000809

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