Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression

Miller, Gregory M.

doi:10.1038/sj/mp/4000921

Cited by 91 publications

(109 citation statements)

References 36 publications

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“…Mill et al (2002) reported decreased levels of DAT1 mRNA levels in post-mortem brain tissue of patients having the 9/9 genotype, compared to the 9/10 and 10/10 genotypes. This result was consistent with an in vivo expression study, using the luciferase reporter system in COS-7 cells, which showed that the 7-and 9-repeat alleles had lower levels of transcription than the 10-repeat allele (Fuke et al, 2001), although opposite results using other experimental systems were also reported (Miller and Madras, 2002). Further functional studies exploring the three genotypes separately and using homogenous populations are needed to resolve these inconsistencies.…”

Section: Discussionsupporting

confidence: 86%

Dopamine Transporter 3′-UTR VNTR Genotype and ADHD: a Pharmaco-Behavioural Genetic Study with Methylphenidate

Joober

Grizenko

Sengupta

et al. 2006

Neuropsychopharmacol

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We sought to test the hypothesis that the variable number of tandem repeat (VNTR) polymorphism in the 3 0 -untranslated region (3 0 -UTR) of the SLC6A3 gene modulates behavior in children with ADHD and/or behavioral response to methylphenidate (MPH). One hundred and fifty-nine children with AHDH (6-12 years) were assessed with regard to the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) and the response of these behaviors to MPH (0.5 mg/kg/day) using a 2-week prospective within-subject (crossover) trial. Based on CGI-Parents, the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3 0 -UTR VNTR polymorphism of SLC6A3, as indicated by a significant (p ¼ 0.017) genotype by treatment two-way interaction. Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele. No genotype or genotype by treatment interaction was observed for CGI-Teachers. These findings support a role for the DAT gene 3 0 -UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD. They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH.

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Section: Discussionsupporting

confidence: 86%

Dopamine Transporter 3′-UTR VNTR Genotype and ADHD: a Pharmaco-Behavioural Genetic Study with Methylphenidate

Joober

Grizenko

Sengupta

et al. 2006

Neuropsychopharmacol

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“…Overexpression studies have generated inconsistent and conflicting results (Fuke et al. 2001; Miller and Madras 2002; Mill et al. 2005; VanNess et al.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies using the overexpression analysis of reporter plasmids that contain either 9 or 10 repeat of VNTR generated inconstant results possibly due to the differences in the cell line used, in the construction of plasmids, and in the total amount of plasmid DNA transfected, all of which could confound the results. One previous study (Miller and Madras 2002) used two different promoters driving the luciferase reporter gene followed by the 9 or 10 repeat of 3′ UTR VNTR and carefully controlled the quality of plasmid DNA preparation and quantification. In that study, both of the two plasmid constructs showed that nine repeats of the VNTR resulted in a higher level of reporter expression which is consistent with our results obtained from human DA neurons.…”

Section: Discussionmentioning

confidence: 99%

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

et al. 2016

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IntroductionThe dopaminergic (DA) system plays important roles in addiction. However, human DA neurons from drug‐dependent subjects were not available for study until recent development in inducible pluripotent stem cells (iPSCs) technology.MethodsIn this study, we produced DA neurons differentiated using iPSCs derived from opioid‐dependent and control subjects carrying different 3′ VNTR (variable number tandem repeat) polymorphism in the human dopamine transporter (DAT or SLC6A3). In addition, the effects of valproic acid (VPA) exposures on iPSC‐derived human DA neurons are also examined.ResultsWe present the first evidence suggesting that the 3′ VNTR polymorphism in the hDAT gene affects DAT expression level in iPSC‐derived human DA neurons. In human DA neurons, which provide an appropriate cellular milieu, VPA treatment alters the expression of several genes important for dopaminergic neuron function including DAT, Nurr1, and TH; this might partly explain its action in regulating addictive behaviors. VPA treatment also significantly increased DA D2 receptor (Drd2) expression, especially in the opioid‐dependent iPSC cell lines.ConclusionsOur data suggest that human iPSC‐derived DA neurons may be useful in in vitro experimental model to examine the effects of genetic variation in gene regulation, to examine the underlying mechanisms in neurological disorders including drug addiction, and to serve as a platform for therapeutic development.

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“…Recently, many reports have shown that the SNP in UTRs could have an impact on mRNA stability, translation efficiency and gene expression [25][26][27][28]. After searching the microRNA database, no target sequence was found.…”

Section: Discussionmentioning

confidence: 99%

c.822+126T>G/C: a novel triallelic polymorphism of the TSSK6 gene associated with spermatogenic impairment in a Chinese population

Su¹,

Zhang²,

Yang³

et al. 2009

Asian J Androl

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Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression

Cited by 91 publications

References 36 publications

Dopamine Transporter 3′-UTR VNTR Genotype and ADHD: a Pharmaco-Behavioural Genetic Study with Methylphenidate

Dopamine Transporter 3′-UTR VNTR Genotype and ADHD: a Pharmaco-Behavioural Genetic Study with Methylphenidate

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

c.822+126T>G/C: a novel triallelic polymorphism of the TSSK6 gene associated with spermatogenic impairment in a Chinese population

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