The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
The human dopamine D4 receptor repeat sequences modulate expression
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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In the citing paper
“Functional significance of this polymorphism has been demonstrated [70–75].”
From Genetics of child aggression, a systematic review (2024) · cites this paper as [73]
In the citing paper
“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]
In the citing paper
“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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Cites
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de Wet, J. R., Wood, K. V., DeLuca, M., Helinski, D. R., & Subramani, S. E. (1987) · Molecular and Cellular Biology · doi:10.1128/mcb.7.2.725 · Cited by 3,088
Multiple dopamine D4 receptor variants in the human population
Tol, H. H. M. V., Wu, C. M., Guan, H.-C., Ohara, K., Bunzow, J. R., Civelli, O., Kennedy, J., Seeman, P., Niznik, H. B., & Jovanovic, V. (1992) · Nature · doi:10.1038/358149a0 · Cited by 955
Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants
Asghari, V., Sanyal, S., Buchwaldt, S., Paterson, A., Jovanovic, V., & Van Tol, H. H. M. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.65031157.x · Cited by 858
Faraone, S., Doyle, A., Mick, E., & Biederman, J. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.7.1052 · Cited by 740
Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder.
LaHoste, G. J., Swanson, J. M., Wigal, S. B., Glabe, C. G., Wigal, T. L., King, N., & Kennedy, J. L. (1996) · PubMed · Cited by 678
A hypervariable segment in the human dopamine receptor D4 (DRD4) gene
Lichter, J. B., Barr, C. L., Kennedy, J. L., Tol, H. H. M. V., Kídd, K. K., & Livak, K. J. (1993) · Human Molecular Genetics · doi:10.1093/hmg/2.6.767 · Cited by 524
Evidence of positive selection acting at the human dopamine receptor D4 gene locus
Ding, Y. C., Chi, H. C., Grady, D., Morishima, A., Kidd, J., Kidd, K., Flodman, P., Spence, M., Schuck, S., Swanson, J., et al. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.012464099 · Cited by 506
The poly(C)-binding proteins: A multiplicity of functions and a search for mechanisms
Makeyev, A. V., & Liebhaber, S. A. (2002) · RNA · doi:10.1017/s1355838202024627 · Cited by 469
The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus
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Cited by
Sorted by citations
Genetics of dopamine receptors and drug addiction: a comprehensive review
Foll, B. L., Gallo, A., Strat, Y. L., Lü, L., & Gorwood, P. A. P. M. (2009) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e3283242f05 · Cited by 395
The molecular genetic architecture of human personality: beyond self-report questionnaires
Ebstein, R. P. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001814 · Cited by 367
Eisenberg, D. T. A., MacKillop, J., Modi, M. E., Beauchemin, J., Dang, D., Lisman, S. A., Lum, J. K., & Wilson, D. S. (2007) · Behavioral and Brain Functions · doi:10.1186/1744-9081-3-2 · Cited by 264
Dreber, A., Apicella, C. L., Eisenberg, D. T. A., Garcia, J. R., Zamore, R. S., Lum, J. K., & Campbell, B. (2009) · Evolution and Human Behavior · doi:10.1016/j.evolhumbehav.2008.11.001 · Cited by 217
Eisenberg, D. T. A., Campbell, B., Gray, P. B., & Sorenson, M. D. (2008) · BMC Evolutionary Biology · doi:10.1186/1471-2148-8-173 · Cited by 197
Metadata
- Authors
- Schoots, O., & Van Tol, H. H. M.
- Affiliations
- Centre for Addiction and Mental Health (CA)
- Venue
- The Pharmacogenomics Journal
- Published
- 2003-10-28
- Volume
- 3
- Issue
- 6
- Pages
- 343-348
- ISSN
- 1470-269X (ISSN-L)
- 1473-1150
- 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
- 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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