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

Hill, M., Anney, Richard ORCID: https://orcid.org/0000-0002-6083-407X, Gill, M. and Hawi, Z. 2010. Functional analysis of intron 8 and 3 ' UTR variable number of tandem repeats of SLC6A3: differential activity of intron 8 variants. Pharmacogenomics Journal 10 (5) , pp. 442-447. 10.1038/tpj.2009.66

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	dopamine transporter; methylphenidate; ADHD; functional variant
Publisher:	Nature Publishing Group
ISSN:	1470-269X
Last Modified:	31 Oct 2022 10:31
URI:	https://orca.cardiff.ac.uk/id/eprint/85239

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