Single nucleotide polymorphisms distinguish multiple dopamine transporter alleles in primates: implications for association with attention deficit hyperactivity disorder and other neuropsychiatric disorders.
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.
Harvard Medical School, Division of Neurochemistry, New England Regional Primate Research Center, One Pine Hill Drive, Southborough, MA 01772-9102, USA.
G M
GM
Miller
R
R
De La Garza
M A
MA
Novak
B K
BK
Madras
D020413:3' Untranslated Regions / Q000235:genetics; D000483:Alleles; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001483:Base Sequence; D001923:Brain Chemistry / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D003001:Cloning, Molecular; D016384:Consensus Sequence; D050483:Dopamine Plasma Membrane Transport Proteins; D005838:Genotype; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012091:Repetitive Sequences, Nucleic Acid
D020413:3' Untranslated Regions; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins