Alternative titles; symbols
HGNC Approved Gene Symbol: DRD5
Cytogenetic location: 4p16.1 Genomic coordinates (GRCh38): 4:9,781,634-9,784,009 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.1 | {Attention deficit-hyperactivity disorder, susceptibility to} | 143465 | Autosomal dominant | 3 |
| {Blepharospasm, primary benign} | 606798 | Autosomal dominant | 3 |
Tiberi et al. (1991) isolated and characterized a rat gene encoding a dopamine receptor that is structurally and functionally similar to the D1 dopamine receptor (DRD1; 126449). The gene encodes a protein of 475 amino acids with structural features that are consistent with G protein-coupled receptors. The expressed protein binds dopaminergic ligands and mediates stimulation of adenylyl cyclase with pharmacologic properties similar to those of the D1 dopamine receptor. In striking contrast to the previously cloned D1 receptor, little or no mRNA for the receptor described here was observed in striatum, nucleus accumbens, olfactory tubercle, and frontal cortex. High levels of mRNA for this receptor were found in distinct layers of the hippocampus, the mamillary nuclei, and the anterior pretectal nuclei, all brain regions that have been shown to exhibit little or no D1 dopamine receptor binding.
Grandy et al. (1991) found that the human DRD5 protein shares 49% sequence identity with the DRD1 protein.
By in situ hybridization studies, Polymeropoulos et al. (1991) showed that the D5 dopamine receptor is neuron specific and that it localizes within limbic regions of the brain.
Beischlag et al. (1995) investigated the expression of the functional DRD5 gene by in situ hybridization of both monkey and human brains using a 5-prime D5-specific riboprobe. They found that DRD5 mRNA was most abundant in discrete cortical areas (layers II, IV, and VI), the dentate gyrus, and hippocampal subfields but they detected very little message in the striatum. Unexpectedly, D5 mRNA antisense riboprobes labeled discrete cell bodies in the pars compacta of the substantia nigra.
Pseudogenes
Weinshank et al. (1991) cloned and characterized the human DRD5 gene and found a second closely related gene, GL39, which was shown to represent a pseudogene. This was the first pseudogene to be described in the G protein-coupled receptor superfamily. It exhibited 94% nucleotide sequence homology to the functional gene and may have arisen from a gene duplication event followed by a mutation approximately 8 million years ago, before the emergence of man. This recently evolved pseudogene is transcribed in the human brain with a tissue distribution similar to that for the closely related functional gene. Grandy et al. (1991) identified 2 pseudogenes which were 98% identical to each other and 95% identical to the DRD5 sequence. Relative to the D5 sequence, both contained insertions and deletions that resulted in several in-frame termination codons. Premature termination of translation was the probable explanation for the failure of these genes to produce receptors in COS-7 and 293 cells even though their messages were transcribed.
Polymeropoulos et al. (1991) found that DRD5, like DRD1, stimulates adenylate cyclase activity.
Grandy et al. (1991) determined that, compared with DRD1, DRD5 displayed a higher affinity for dopamine and was able to stimulate a biphasic rather than a monophasic intracellular accumulation of cAMP.
Liu et al. (2000) demonstrated that GABA-A ligand-gated channels complex selectively with dopamine D5 receptors through the direct binding of the D5 carboxy-terminal domain with the second intracellular loop of the GABA-A gamma-2 (short) receptor subunit (137164). This physical association enables mutual inhibitory functional interactions between these receptor systems. Liu et al. (2000) concluded that the data highlight a previously unknown signal transduction mechanism whereby subtype-selective G protein-coupled receptors dynamically regulate synaptic strength independently of classically defined second-messenger systems, and suggest a possible framework in which to view these receptor systems in the maintenance of psychomotor disease states, particularly schizophrenia (181500).
Li et al. (2008) found that pharmacologic activation of DRD5 in human renal proximal tubule cells and HEK cells increased degradation of the glycosylated form of the angiotensin II type 1 receptor (AGTR1; 106165), a prohypertensive protein, via the ubiquitin pathway.
Beischlag et al. (1995) described the genomic organization of the 5-prime flanking region and promoter of the human dopamine D5 receptor gene. The gene contains 2 exons separated by a small and variably sized intron (of either 179 or 155 bp). The transcriptional start site lies 2,125 bp upstream from the translational initiation site. Promoter deletion analysis indicated that the DRD5 gene promoter contains a positive modulator from nucleotide position -199 to -182 and a negative modulator from position -500 to -251 relative to the transcription initiation site.
Using PCR, Polymeropoulos et al. (1991) studied the segregation of the DRD5 gene in human/rodent somatic cell hybrids and showed that the gene is located on chromosome 4. By in situ hybridization, Tiberi et al. (1991) mapped the human DRD5 gene, which they called D1B, to chromosome 4p16.3.
Using gene-specific amplification with PCR on a panel of somatic cell hybrids carrying different human chromosomes, Eubanks et al. (1992) mapped the DRD5 gene to 4p. Further localization was carried out through the isolation and analysis of yeast artificial chromosomes (YAC), fluorescence in situ suppression hybridization to human metaphase chromosomes, and analysis of a panel of somatic cell hybrids subdividing human chromosome 4 into 9 regions. In this way, DRD5 was located at 4p15.33-p15.1, centromeric to the location of the Huntington disease locus (143100).
By combining in situ hybridization results with sequence analysis of PCR products from microdissected chromosomes, somatic cell hybrids, and radiation hybrids, Grandy et al. (1992) assigned the DRD5 gene to 4p16.1 and the 2 pseudogenes, DRD5P1 and DRD5P2, to 2p11.2-p11.1 and 1q21.1, respectively.
Sherrington et al. (1993) cloned the DRD5 receptor and used it to map the DRD5 gene by linkage studies in 39 CEPH pedigrees. Combining their data with those of others, they placed the DRD5 gene at 4p15.3.
The mouse Drd5 gene is located on chromosome 5 (Wilkie et al., 1993). Grosson et al. (1994) mapped the murine homolog of dopamine receptor D5 to mouse chromosome 5 in a continuous linkage group with 18 human chromosome 4 loci.
Sherrington et al. (1993) identified a polymorphic microsatellite, which they named DRD5 (CT/GT/GA)n (126453.0001), and determined that there are 12 alleles of differing sizes.
Benign Essential Blepharospasm, Susceptibility to
Misbahuddin et al. (2002) performed association studies between focal dystonia blepharospasm (606798) and 10 previously reported polymorphisms within the dopamine transporter (DAT) gene (SLC6A3; 126455) and dopamine receptor genes D1-5. Allele 2 of the dinucleotide repeat in the D5 receptor gene (126453.0001) was found to have an increased frequency in blepharospasm cases compared with controls.
Attention-Deficit/Hyperactivity Disorder, Susceptibility to
Daly et al. (1999) reported a significant association between attention-deficit/hyperactivity disorder (ADHD; 143465) and the 148-bp allele of a microsatellite located 18.5 kb 5-prime to the DRD5 gene. Subsequent studies of this (CA)n repeat marker showed nonsignificant trends toward association with the same allele. Although there was no evidence to suggest that the D5 microsatellite is itself functional, the association reported by Daly et al. (1999) was in the opinion of Lowe et al. (2004) too strong to be ignored. Therefore, they hypothesized that if the association with ADHD were true, the microsatellite may be in linkage disequilibrium (LD) with 1 or more functional variants. To this end, they invited all known groups with samples based on parent-proband trios to genotype their samples for the marker and present their data for analysis. Fourteen independent samples were analyzed individually and, in the absence of heterogeneity, analyzed as a joint sample. The joint analysis showed association with the DRD5 locus (p = 0.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appeared to be confined to the predominantly inattentive and combined clinical subtypes.
Associations Pending Confirmation
For discussion of a possible association between primary cervical focal dystonia (see, e.g., DYT1, 128100) and variation in the DRD5 gene, see 126453.0001.
By analyzing short-read mapping depth for 159 human genomes, Sudmant et al. (2010) demonstrated accurate estimation of absolute copy number for duplications as small as 1.9 kb pairs, ranging from 0 to 48 copies. Sudmant et al. (2010) identified 4.1 million 'singly unique nucleotide' positions informative in distinguishing specific copies and used them to genotype the copy and content of specific paralogs within highly duplicated gene families. These data identified human-specific expansions in genes associated with brain development, such as GPRIN2 (611240) and SRGAP2 (606524), which have been implicated in neurite outgrowth and branching. Also included were the brain-specific HYDIN2 gene (610813), associated with micro- and macrocephaly; DRD5, a dopamine D5 receptor; and the GTF2I (601679) transcription factors, whose deletion has been associated with visual-spatial and sociability deficits among Williams-Beuren syndrome (194050) patients, among others. The data of Sudmant et al. (2010) also revealed extensive population genetic diversity, especially among the genes NPEPPS (606793), UGT2B17 (601903), and NBPF1 (610501), as well as LILRA3 (604818), which is the most highly stratified gene by copy number in the human genome. In addition, Sudmant et al. (2010) detected signatures consistent with gene conversion in the human species.
Li et al. (2008) found that Drd5-null mice developed hypertension associated with increased expression of Agtr1 in renal cortical tubules. Treatment of the mice with the AGTR1 antagonist losartan normalized blood pressure. Activation of DRD5 in human renal proximal tubule cells increased degradation of glycosylated AGTR1 in proteasomes via activation of the ubiquitin pathway. Li et al. (2008) concluded that the hypertension in Drd5-null mice was caused in part by increased Agtr1 expression resulting from the absence of the negative effect of Drd5 on Agtr1, consistent with a novel mechanism whereby blood pressure is regulated by the interaction of 2 counterregulatory G protein-coupled receptors, DRD5 and AGTR1.
Sherrington et al. (1993) identified a polymorphic microsatellite, which they named DRD5 (CT/GT/GA)n, and determined that there are 12 alleles of differing sizes.
Brancati et al. (2003) noted that this polymorphic microsatellite is located 5-prime to and outside of the coding region of the DRD5 gene. This suggests that it may not have a functional role, but rather may be in linkage disquilibrium with a functional variant that could explain its association with certain disorders.
Blepharospasm, Benign Essential, Susceptibility to
Misbahuddin et al. (2002) performed an association study involving the DRD5 gene and several related genes in 88 patients with blepharospasm (606798) and compared the results with those in 100 control subjects recruited from patients attending the same hospital for nonneurologic conditions. Significant association was found for allele 2 (154-bp allele) of the dinucleotide repeat in the D5 receptor gene; p = 0.009.
Among 100 German and 121 French patients with idiopathic focal dystonia, including blepharospasm and torticollis, Sibbing et al. (2003) found no association with allele 2 or allele 6 of the DRD5 polymorphism.
Dystonia, Primary Focal Cervical
In a case-control association study of 100 patients with primary cervical focal dystonia (see, e.g., DYT1, 128100) and 100 controls in the U.K., Placzek et al. (2001) found that carriage of allele 2 (154 bp) was associated with cervical dystonia. It was found in 13 patients with dystonia and in 2 controls (p = 0.004). In contrast, allele 6 (146 bp) was found in 8 patients and in 29 controls (p = 0.0003), implying a possible protective effect. However, only the result for D5 allele 6, with a possible protective effect, remained significant when correction was made from multiple comparisons using the Bonferroni method.
Brancati et al. (2003) performed a case-control study of this microsatellite polymorphism in 104 Italian patients with cervical dystonia and 104 controls. They found an association between dystonia and allele 4 (150 bp), which was found in 27 cases compared to 12 controls (odds ratio (OR) of 2.44, p = 0.01). Allele 10 (138 bp) showed a possible protective effect, present in 20 cases and 33 controls (OR of 0.56, p = 0.06). No association was found for allele 2 or 6. Brancati et al. (2003) noted that the specific alleles they identified as conferring a possible association differed from those of Placzek et al. (2001). Brancati et al. (2003) suggested caution in interpreting the results, but noted that there may be evidence supporting the involvement of the dopamine pathway in the pathogenesis.
Daly et al. (1999) and Lowe et al. (2004) demonstrated an association between ADHD (143465) and a common 148-bp allele of a microsatellite (CA)n marker located 18.5 kb 5-prime of the DRD5 gene. They considered it unlikely that this was a functional variant and that it was more probable that the microsatellite is in linkage disequilibrium with the true functional variant (or variants) located in or close to the DRD5 gene.
Kustanovich et al. (2004) genotyped a large multiplex sample of ADHD-affected children and their parents for polymorphisms in genes reported to be associated with ADHD, including DRD5, and analyzed the results using the transmission disequilibrium test. The dinucleotide repeat polymorphism near the DRD5 gene showed an association with ADHD, with biased nontransmission of the 146-bp allele and a trend toward excess transmission of the 148-bp allele. The DRD5 146-bp allele showed an estimated genotype relative risk of 1.7.
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