The human dopamine D4 receptor repeat sequences modulate expression

Schoots, O; Van Tol, H H M

doi:10.1038/sj.tpj.6500208

Cited by 213Neurotransmitter Receptor Influence on BehaviorGenetic Associations and EpidemiologySchizophrenia research and treatment

The human dopamine D4 receptor repeat sequences modulate expression

Schoots, O, Van Tol, H H M·2003·The Pharmacogenomics Journal

DOI 10.1038/sj.tpj.6500208

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Abstract

Genetic studies have implicated a polymorphic repeat sequence in exon 3 of the human dopamine D4 receptor in various behavioral and psychiatric disorders. Functionally various repeat variants are nearly identical, but whether these have different effects on gene expression has not been studied. To study the role of the repeat sequences on expression independently from its structural and functional effects at the protein level, we introduced these sequences immediately upstream of the promoter and in the 3' untranslated region of a luciferase reporter vector. In this report, we demonstrate that the repeat sequence can both modulate promoter activity and alter expression post-transcriptionally. The repeat sequence can serve as a substrate for a nuclear binding factor and all the three repeat variants can suppress promoter activity. Placement of the three repeat variants downstream from the luciferase gene in the expression vector shows, however, that the D4.7 repeat sequence has significantly suppressed expression of the reporter compared to the D4.2 and D4.4 repeats, likely via mechanisms involving RNA stability or translational efficiency. These data indicate that the various D4 repeat sequences have different effects on expression, which may explain its potential role in behavioral disorders.

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Functional significance of the DRD4 48-bp exon III VNTR polymorphism has been demonstrated.
“Functional significance of this polymorphism has been demonstrated [70–75].”
From Genetics of child aggression, a systematic review (2024) · cites this paper as [73]
The 7 R DRD4 allele reduces in-vitro DRD4 expression and is less likely to form heterodimers with the dopamine D2 receptor, while the 4 R allele appears less responsive to quinpirole-mediated DRD4 upregulation.
“The 7 R has been shown to reduce in-vitro DRD4 expression [73] and to be less likely to form heterodimers with the dopamine D2 receptor [76], while the 4 R allele appears to be less responsive to quinpirole-mediated DRD4 upregulation [74].”
From Genetics of child aggression, a systematic review (2024) · cites this paper as [73]
The 7-repeat allele is associated with increased reward-related reactivity in ventral striatum relative to the 4-repeat allele.
“and has been associated with increased reward related reactivity in ventral striatum, relative to the 4-repeat allele (Schoots and Van Tol 2003; Forbes, Brown et al. 2009; Stice, Yokum et al. 2012).”
From Developmental imaging genetics: Linking dopamine function to adolescent behavior (2014) · cites this paper as Schoots and Van Tol 2003

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Authors: Schoots, O., & Van Tol, H. H. M.
Affiliations: Centre for Addiction and Mental Health (CA)
Venue: The Pharmacogenomics Journal
Publisher: Springer Science and Business Media LLC
Published: 2003-10-28
Volume: 3
Issue: 6
Pages: 343-348
ISSN: 1470-269X (ISSN-L)
1473-1150
DOI: 10.1038/sj.tpj.6500208
OpenAlex: W2015176102
Cited by: 213
References: 32
Citations by year: 2026: 1 · 2025: 1 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 12 · 2017: 7 · 2016: 9 · 2015: 16 · 2014: 15 · 2013: 17 · 2012: 16
FWCI: 1.15
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: The Pharmacogenomics Journal (publishedVersion)
PubMed (publishedVersion)
Funders: Canada Research Chairs
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords: dopamine D4 receptor, DRD4, repeat polymorphism, exon 3, promoter activity, 3' untranslated region, post-transcriptional regulation, RNA stability, translation efficiency, gene expression regulation, mental illness
MeSH terms: Analysis of Variance, Gene Expression Regulation, HeLa Cells, Humans, Repetitive Sequences, Nucleic Acid, Receptors, Dopamine D2, Receptors, Dopamine D4

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The human dopamine D4 receptor repeat sequences modulate expression

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