The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS

doi:10.1016/0888-7543(92)90222-E

Genomics

Volume 13, Issue 1, May 1992, Pages 208-210

https://doi.org/10.1016/0888-7543(92)90222-E Get rights and content

Abstract

Dopaminergic pathophysiology is important in several psychiatric illnesses. The recently cloned D₄ dopamine receptor gene (DRD4) shows considerable homology to the D₂ and D₃ dopamine receptors (DRD2 and DRD3); pharmacologically, its affinity for the atypical antipsychotic clozapine is much higher than that of these other dopamine receptors. Probe pB28 for this locus recognizes an informative HincII polymorphism. We typed this polymorphism on several large reference families (a total of about 271 individuals) to place DRD4 in the genetic linkage map. Pairwise linkage analysis (using ILINK) provided evidence for close linkage to the distal 11p loci tyrosine hydroxylase (TH) and the Harvey ras oncogene (HRAS). We used our version of LINKMAP adapted to run under distributed parallel processing (Linda-LINKMAP) for an analysis moving DRD4 across a fixed map with HRAS set 3.8 cM distal to TH. This localized DRD4 close to HRAS, with no crossovers observed between those loci and a maximum lod score of 19.9 (2 cM distal to HRAS). The one LOD unit support interval extends from about 1 cM proximal to HRAS to 8 cM distal to HRAS. Crossovers identified in one kindred place DRD4 distal to TH, providing further evidence for its location close to HRAS, making DRD4 one of the most telomeric of 11p markers. (This also places DRD4 in band 11p15.5.)

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Genetic polymorphism of dopamine receptor D4 (DRD4) gene in ten Indian rhesus macaques (Macaca mulatta mulatta)
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Among the three “D2-like” dopamine receptors, the D4 dopamine receptor is a 7-transmembrane G-protein-coupled dopamine receptor encoded by the dopamine receptor D4 (DRD4) gene, found in the limbic system, frontal cortex and other areas of the brain (Strange, 1994; Seeman, 1995; Van Tol, 1996; Seaman et al., 2000). In humans, DRD4 gene is located on chromosome 11p15.5 (Gelernter et al., 1992; Takeuchi et al., 2015) and this gene has four exons (Seaman et al., 2000). In rhesus macaques, DRD4 gene is located on chromosome number 14.
Advances in molecular genetical research have revealed a new platform for studying the configuration and activity correlations of dopamine receptor D4 (DRD4) gene in the non-human primates and human. Among the other five dopamine receptor genes, dopamine receptor D4 (DRD4) gene has variable number of tandem repeats which are polymorphic and located in the third cytoplasmic loop of the receptor. These polymorphism are expressed in the repeat numbers of 48-base pair (bp) sequence coding for 16 amino acids. This study is designed to observe the genetic polymorphism of dopamine receptor D4 gene within the ten Indian rhesus macaques (Macaca mulatta mulatta). This research is also planned to compare the genetic sequences among the Indian rhesus macaque DRD4 genetic sequences of our recent study, rhesus macaque DRD4 gene reference sequence provided by ENSEMBL genome browser and human DRD4 gene reference sequence provided by National Center for Biotechnology Information (NCBI), USA. In our study, only DRD4 5-repeat allele variant is observed in all the ten selected Indian rhesus macaques. Sequencing data of DRD4 gene of these rhesus macaques indicate that rhesus macaques exhibit 48-bp tandem repeats in the DRD4 receptor gene which is similar to humans and there is intraspecies variability within the rhesus macaque DRD4 genetic sequences.
Clinical and neurobiological factors in the management of treatment refractory attention-deficit hyperactivity disorder
2016, Progress in Neuro-Psychopharmacology and Biological Psychiatry
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Considering the gene structure of DAT1 and recent findings of an association of DAT1 with ADHD clinical phenotype, future studies for additional gene regions will be needed. The DRD4 gene has been mapped to chromosome 11p15.5 (Gelernter et al., 1992) and is also regarded as a leading candidate gene for ADHD. Biochemically, the 4-repeat protein has a significantly less blunted response to dopamine than do the 2-repeat or 7-repeat proteins (Asghari et al., 1995).
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent mental disorder of childhood, which often continues into adolescence and adulthood. Stimulants such as methylphenidate (MPH) and non-stimulants such as atomoxetine are effective medications for the treatment of ADHD. However, about 30% of patients do not respond to these medications. Pharmacological treatment for ADHD, although highly effective, is associated with marked variabilities in clinical response, optimal dosage needed and tolerability. This article provides an overview of up-to-date knowledge regarding the clinical and neurobiological factors which contribute to and help predict treatment-refractory ADHD. Pharmacogenetic, pharmacogenomics and neuroimaging studies are still controversial with respect to determining the associations between response to medication and genetic factors, thereby resulting in hypotheses that differences in the genetic factors and neuroimaging findings contribute to treatment outcome. Much research on the potential role of genotype in pharmacological effects has focused on the catecholaminergic gene related to executive functions. Many neuroimaging studies have also reported a relationship between treatment response and common patterns of brain structure or activity according to various genetic polymorphisms. When children, adolescents and adults with ADHD do not respond to MPH, we should consider additional pharmacological options, including other classes of psychostimulants, the nonstimulant atomoxetine, bupropion, tricyclic antidepressant, clonidine, guanfacine and lisdexamphetamine. Prudent choice of an appropriate medication and active engagement of children, parents, and teachers in daily management may help to ensure long-term adherence. Therefore, additional research might help to optimize the treatment of children, adolescents and adults with ADHD and to find new options for the treatment of patients who do not respond to stimulants and the other medications. Because these findings should be interpreted cautiously, further studies are needed to elucidate these issues more clearly.
Dopamine D4 receptor deficiency in mice alters behavioral responses to anxiogenic stimuli and the psychostimulant methylphenidate
2013, Pharmacology Biochemistry and Behavior
Citation Excerpt :
The dopamine D4 receptor (D4R), a D2-like G protein-coupled receptor is primarily expressed in the cerebral cortex and has a distinct pharmacological profile (Van Tol et al., 1991) that has made it the focus of atypical antipsychotic medication development (Wong and Van Tol, 2003). The human D4R protein is coded for by a gene (DRD4) composed of 4 exons located on the short arm of chromosome 11 (11p15.5) (Gelernter et al., 1992). Unlike the other four dopamine receptor genes, the sequence of the DRD4 is highly variable (Van Tol et al., 1992).
An allele of the human dopamine D4 receptor (D4R) gene (DRD4), containing seven tandem repeats of a 48-base nucleotide sequence (DRD4.7), has been reproducibly found in novelty seekers, substance abusers, and individuals with attention-deficit hyperactivity disorder. One hypothesis predicts the resultant protein product of the DRD4.7 polymorphism is deficient in G protein-coupled signaling. If attenuated D4R signaling contributes to these complex behaviors, then wild-type (WT) mice and mice completely lacking D4Rs (D4R KO) might be expected to display significantly different behavioral responses to stimuli known to affect dopamine signaling, such as novelty or psychostimulants. Adolescent male D4R KO mice exhibited greater locomotor activity and spent less time in the anxiogenic center of a novel open field environment than WT littermates. The presence of D4Rs had no effect on emergence into a novel environment from a sheltered space or exploration of a novel object. Low doses of acute methylphenidate (MP) had no effect on the exploration of a novel object, but dose-dependently increased the latency to emerge into a novel environment from a sheltered space. WT and D4R KO mice responded differently to high doses of acute MP, displaying significantly elevated locomotor activity and reduced stereotypy relative to WT mice. Chronic MP treatment produced enhanced locomotor sensitization in D4R KO mice, however this effect could not be fully recapitulated using the putative D4R antagonist L-745-870. These studies suggest that the roles of D4R signaling in novelty-seeking behaviors and the response to psychostimulants are not as clear as previously reported, and that some of these effects may be due to developmental compensatory effects as a consequence of lost D4R expression. If the DRD4.7 variant results in deficient D4R signaling in vivo, this may contribute to an elevated risk of sensitization to drugs of abuse including psychostimulants used to treat ADHD.
Depression and the role of genes involved in dopamine metabolism and signalling
2010, Progress in Neurobiology
Major depressive disorder (MDD) is a common psychiatric disorder and leading cause of disability worldwide. It is associated with increased mortality, especially from suicide. Heritability of MDD is estimated around 40%, suggesting that genotyping is a promising field for research into the development of MDD. According to the dopamine theory of affective disorders, a deficiency in dopaminergic neurotransmission may play a role in the major symptoms of MDD. Specific polymorphisms in genes that affect dopamine transmission could increase susceptibility to MDD. To determine the extent to which these genes influence vulnerability to MDD, we discuss genes for crucial steps in dopamine neurotransmission: synthesis, signalling and inactivation. The val158met polymorphism of the COMT gene exemplifies the lack of consensus in the literature: although it is one of the most reported polymorphisms that relates to MDD vulnerability, its role is not corroborated by meta-analysis. Gene–gene interactions and gene–environment interactions provide more explanatory potential than single gene associations. Two notable exceptions are the DRD4 and DAT gene: both have variable tandem repeat polymorphisms which may have a “single gene” influence on susceptibility to MDD.
Minor genetic variants of the dopamine D4 receptor (DRD4) polymorphism are associated with novelty seeking in healthy Japanese subjects
2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Although an association between the dopamine receptor D4 (DRD4) gene and personality traits had been previously investigated, results from previous studies were not conclusive. This may be due to the method of grouping used, which categorized the gene population into two groups based on the length of the variable number of tandem repeats (VNTR) in exon 3. In the present study, we categorized 616 healthy Japanese subjects into more than two groups by further subdividing the DRD4 48-bp VNTR polymorphism, and compared Temperament and Character Inventory (TCI) scores among the groups. A significant difference was found between the DRD4 48-bp VNTR polymorphism and novelty seeking (p = 0.016). The novelty-seeking scores in the subjects carrying the 5/5 genotype were significantly higher than in those carrying the 2/2 genotype (p = 0.002) or the 4/4 genotype (p = 0.005). However, when the conventional method of grouping was used (i.e., short alleles vs. long alleles), there were no significant associations between the DRD4 VNTR polymorphism and any TCI scores. Our results suggest that minor 5-repeat allele is associated with high novelty-seeking scores in healthy Japanese subjects.
Approach to the genetics of alcoholism: A review based on pathophysiology
2008, Biochemical Pharmacology
Citation Excerpt :
Among other loci with relevance to the dopaminergic function, the dopamine D4 receptor gene (DRD4) shares molecular characteristics with DRD2[93]. It is located on chromosome 11p15.5 [94]. After a polymorphism with a 48 base pair variable number of tandem repeats (VNTR) had been identified in the exon 3 of DRD4 (DRD4 E8 48-bp VNTR), 2–11 repeats were found with variable frequencies in several populations [95–97].
Alcohol dependence is a common disorder with a heterogenous etiology. The results of family, twin and adoption studies on alcoholism are reviewed. These studies have revealed a heritability of alcoholism of over 50%. After evaluating the results, it was epidemiologically stated that alcoholism is heterogenous complex disorder with a multiple genetic background. Modern molecular genetic techniques allow examining specific genes involved in the pathophysiology of complex diseases such as alcoholism. Strategies for gene identification are introduced to the reader, including family-based and association studies. The susceptibility genes that are in the focus of this article have been chosen because they are known to encode for underlying mechanisms that are linked to the pathophysiology of alcoholism or that are important for the pharmacotherapeutic approaches in the treatment of alcohol dependence. Postulated candidate genes of the metabolism of alcohol and of the involved neurotransmitter systems are introduced. Genetic studies on alcoholism examining the metabolism of alcohol and the dopaminergic, GABAergic, glutamatergic, opioid, cholinergic and serotonergic neurotransmitter systems as well as the neuropeptide Y are presented. The results are critically discussed followed by a discussion of possible consequences.

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Short communicationThe D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS

Abstract

Comp. Biomed. Res

Genomics

Bipolar affective disorder linked to DNA markers on chromosome 11

Nature

Generative communication in Linda

ACM Trans. Prog. Lang. Sys

Gilles de la Tourette syndrome is not linked to D2 dopamine receptor

Arch. Gen. Psych

The human dopamine D2 receptor gene is located in chromosome 11 at q22–q23 and identifies a Taq I polymorphism

Am. J. Hum. Genet

A human D1 dopamine receptor gene is located on chromosome 5 at q35.1 and identifies an EcoRI RFLP

Am. J. Hum. Genet

Short communication
The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS

Gilles de la Tourette syndrome is not linked to D₂ dopamine receptor

A human D₁ dopamine receptor gene is located on chromosome 5 at q35.1 and identifies an EcoRI RFLP