Functional analysis of intron 8 and 3' UTR variable number of tandem repeats of SLC6A3: differential activity of intron 8 variants

Matthew James Hill, Richard J Anney, Michael Gill, Ziarih Hawi

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)

Abstract

Association studies have found that variation in the dopamine transporter gene (SLC6A3) is important in the susceptibility to attention-deficit hyperactivity disorder (ADHD) and response to methylphenidate treatment. An understanding of the biological mechanisms underlying these associations is still inconclusive. We assessed the relative activity of variable number tandem repeat (VNTR) alleles of SLC6A3 under basal and stimulated cellular conditions, as well as in the presence of pharmacological blockade of the dopamine transporter using gene-reporter constructs. The intron 8 VNTR 5-repeat allele is more active than the 6-repeat allele. In the presence of forskolin, both alleles were significantly induced. Blockade of the dopamine transporter did not influence activity of either allelic construct. No difference in activity between 9-and 10-repeat alleles of the 3 -untranslated region VNTR was observed under any experimental condition. These data suggest that the intron 8 VNTR is a functional variant with an ADHD susceptibility allele having reduced activity. The lack of enhanced allele-specific activity in response to treatment regimes suggests that differential activity under basal conditions is the primary mode of action
Original languageEnglish
Pages (from-to)442 - 447
Number of pages6
JournalThe Pharmacogenomics Journal
Volume10
Issue number5
DOIs
Publication statusPublished - 2010
Externally publishedYes

Cite this

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title = "Functional analysis of intron 8 and 3' UTR variable number of tandem repeats of SLC6A3: differential activity of intron 8 variants",
abstract = "Association studies have found that variation in the dopamine transporter gene (SLC6A3) is important in the susceptibility to attention-deficit hyperactivity disorder (ADHD) and response to methylphenidate treatment. An understanding of the biological mechanisms underlying these associations is still inconclusive. We assessed the relative activity of variable number tandem repeat (VNTR) alleles of SLC6A3 under basal and stimulated cellular conditions, as well as in the presence of pharmacological blockade of the dopamine transporter using gene-reporter constructs. The intron 8 VNTR 5-repeat allele is more active than the 6-repeat allele. In the presence of forskolin, both alleles were significantly induced. Blockade of the dopamine transporter did not influence activity of either allelic construct. No difference in activity between 9-and 10-repeat alleles of the 3 -untranslated region VNTR was observed under any experimental condition. These data suggest that the intron 8 VNTR is a functional variant with an ADHD susceptibility allele having reduced activity. The lack of enhanced allele-specific activity in response to treatment regimes suggests that differential activity under basal conditions is the primary mode of action",
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Functional analysis of intron 8 and 3' UTR variable number of tandem repeats of SLC6A3: differential activity of intron 8 variants. / Hill, Matthew James; Anney, Richard J; Gill, Michael; Hawi, Ziarih.

In: The Pharmacogenomics Journal, Vol. 10, No. 5, 2010, p. 442 - 447.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Functional analysis of intron 8 and 3' UTR variable number of tandem repeats of SLC6A3: differential activity of intron 8 variants

AU - Hill, Matthew James

AU - Anney, Richard J

AU - Gill, Michael

AU - Hawi, Ziarih

PY - 2010

Y1 - 2010

N2 - Association studies have found that variation in the dopamine transporter gene (SLC6A3) is important in the susceptibility to attention-deficit hyperactivity disorder (ADHD) and response to methylphenidate treatment. An understanding of the biological mechanisms underlying these associations is still inconclusive. We assessed the relative activity of variable number tandem repeat (VNTR) alleles of SLC6A3 under basal and stimulated cellular conditions, as well as in the presence of pharmacological blockade of the dopamine transporter using gene-reporter constructs. The intron 8 VNTR 5-repeat allele is more active than the 6-repeat allele. In the presence of forskolin, both alleles were significantly induced. Blockade of the dopamine transporter did not influence activity of either allelic construct. No difference in activity between 9-and 10-repeat alleles of the 3 -untranslated region VNTR was observed under any experimental condition. These data suggest that the intron 8 VNTR is a functional variant with an ADHD susceptibility allele having reduced activity. The lack of enhanced allele-specific activity in response to treatment regimes suggests that differential activity under basal conditions is the primary mode of action

AB - Association studies have found that variation in the dopamine transporter gene (SLC6A3) is important in the susceptibility to attention-deficit hyperactivity disorder (ADHD) and response to methylphenidate treatment. An understanding of the biological mechanisms underlying these associations is still inconclusive. We assessed the relative activity of variable number tandem repeat (VNTR) alleles of SLC6A3 under basal and stimulated cellular conditions, as well as in the presence of pharmacological blockade of the dopamine transporter using gene-reporter constructs. The intron 8 VNTR 5-repeat allele is more active than the 6-repeat allele. In the presence of forskolin, both alleles were significantly induced. Blockade of the dopamine transporter did not influence activity of either allelic construct. No difference in activity between 9-and 10-repeat alleles of the 3 -untranslated region VNTR was observed under any experimental condition. These data suggest that the intron 8 VNTR is a functional variant with an ADHD susceptibility allele having reduced activity. The lack of enhanced allele-specific activity in response to treatment regimes suggests that differential activity under basal conditions is the primary mode of action

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