Cloning of the Human Dopamine D5 Receptor Gene and Identification of a Highly Polymorphic Microsatellite for the DRD5 Locus That Shows Tight Linkage to the Chromosome 4p Reference Marker RAF1P1

Sherrington, Robin; Mankoo, Baljinder S.; Attwood, J.; Kalsi, G; Curtis, David; Buetow, Kenneth H.; Povey, Sue; Gurling, Hugh

doi:10.1006/geno.1993.1489

Cited by 65 publications

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“…23 The (CA) n polymorphism located near the DRD5 gene was genotyped according to previous methods. 2 For the detection of the A1051G DNA variant, a 651-bp PCR fragment of the DRD5 gene was amplified with the following primers: DRD5-G: GCC TTG GTC ATG GTC GGC CTG GCA; DRD5-T: CCA GCA GCT GGG CAA ACA CCT TCT GA as previously described. 8 Amplification proceeded after an initial denaturation step of 4 min at 95°C followed by 35 cycles of 94°C for 30 s, 57°C for 30 s and extension at 72°C for 30 s. A final extension step was added at 72°C for 10 min.…”

Section: Diagnostic Criteriamentioning

confidence: 99%

“…1 Preferential transmission was reported for the 148-bp allele of the (CA) n repeat polymorphism located in the region of the gene and within the same cosmid. 2 This allele was reported to be transmitted 90 times compared to 54 times that it was not transmitted (P value Ͻ0.01).…”

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confidence: 99%

“…The allele frequencies were similar to published reports for Caucasian populations. 2,6 We used the transmission disequilibrium test (TDT) to determine if biased transmission occurred for the alleles at this polymorphism (Table 2). Using the allele-wise test (compares the number of transmissions of a particular allele vs any other allele compared to the number of times that the allele is not transmitted), we did not observe significant evidence for the biased transmission of the 148-bp allele as previously reported, however, there was a trend for the transmission of this allele to the ADHD children.…”

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Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor

et al. 2000

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A recent study has suggested a possible association of a polymorphism near the dopamine D5 receptor gene (DRD5) and attention-deficit hyperactivity disorder. 1 The polymorphism studied was a (CA)n repeat located in the cosmid containing the D5 receptor gene 2 and the allele that was reported to be associated with attention-deficit hyperactivity disorder (ADHD) was the 148-bp allele. In this study we sought to replicate this finding by testing for biased transmission of the alleles at this same polymorphism in a sample of 92 families with an ADHD proband. We did not observe significant evidence for biased transmission of the 148-bp allele, however we did observe biased transmission of two other alleles, the 136-bp allele and the 146-bp allele. For these two alleles the bias was for these two alleles not to be transmitted to the ADHD children. The number of informative transmissions for these two alleles was small, therefore it would be premature to make any conclusions from our study concerning the role of DRD5 in ADHD. Molecular Psychiatry (2000) 5, 548-551.The dopamine receptor D5, located on chromosome 4p15.1-p15.3, 3 is a member of the guanine nucleotidebinding (G-protein) receptors family and is close in structure to the D1 receptor. 4,5 Both the D1 and D5 receptors stimulate adenyl cyclase activity via G-protein coupling however the D5 receptors have a 10-fold higher affinity for dopamine than do the D1 receptors. 4,5 An association with an allele at the dopamine D5 receptor locus (DRD5) and ADHD has been reported using a sample of 91 nuclear families (69 trios and 22 parent-proband pairs) using the haplotype relative risk analysis and the transmission disequilibrium test.

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Section: Diagnostic Criteriamentioning

confidence: 99%

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Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor

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“…6 DRD5 was cloned and mapped to 4p15.1-16.1 7,8 and more recently the promoter region was characterised. 9 The precise location of DRD5 was first assigned by Sherrington et al 10 who isolated a microsatellite (DRD5-M) from a cosmid clone containing DRD5 and demonstrated tight linkage to the chromosome 4p reference marker RAF1P1. The published CEPH-Average map shows DRD5 lying between D4S394 and D4S403 (Genome DataBase) and this position agrees with its location on a physical YAC map of the region (Research Genetics, Huntsville, AL, USA).…”

Section: Introductionmentioning

confidence: 99%

A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder

et al. 1998

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There are several lines of evidence which suggest that chromosome 4p may contain a major susceptibility locus for the functional psychoses. We previously reported a family (family 50) with cases of schizophrenia and schizoaffective disorder which gave maximum lod scores of 1.96 and 1.84 respectively with the markers D4S403 and a microsatellite near to DRD5 (DRD5-M). More recently Blackwood and co-workers described a family segregating bipolar and unipolar affective disorders which gives a maximum lod score of 4.1 with the marker D4S394, which lies 10 cM from D4S403. They obtained a combined maximum lod of 3.3 in their total sample of 12 bipolar families and found significant evidence of heterogeneity ( 2 = 18.8, df = 2, P = 0.00008). Here we report the results of a linkage study of chromosome 4p markers in a sample of 24 multiply affected families with schizophrenia and related disorders. We obtained an overall maximum lod of 1.12 with D4S403 under both dominant and recessive modes of transmission, with no statistical support for heterogeneity within our sample. Examination of family by family data shows that only family 50 appears to show linkage at this locus. However, a discrepancy exists since our study examined families fulfilling criteria for a linkage study of schizophrenia while Blackwood et al examined families included in a genetic linkage study of bipolar disorder. This may be explained by the clinical features displayed by members of family 50, which show that all the affected members have some affective symptoms. It is therefore possible that a broad phenotype including unipolar depression, bipolar disorder, schizoaffective disorder and schizophrenia when accompanied by significant affective symptoms can result from mutations within a gene in this region. The dopamine D5 receptor gene lies within the region identified by the linkage studies and is therefore a major candidate for the putative disease gene. In family 50 we have looked for mutations of DRD5 by sequence analysis of the coding region and single stranded conformational polymorphism (SSCP) analysis of the promoter. SSCP analysis of the coding and promoter regions have also been carried out in unrelated cases of DSM-IIIR schizophrenia. Finally association studies of the (TC) n repeat in the promoter and schizophrenia, and DRD5-M and bipolar disorder were performed. These studies provided no further evidence supporting the possibility that mutations in DRD5 give rise to the linkage findings or are acting as susceptibility loci in schizophrenia or bipolar disorder.

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“…18 We have used a CA repeat isolated from a cosmid clone which contains the DRD5 gene. 19 To avoid possible population stratification in the sampling of cases and controls we used the haplotypebased haplotype relative risk method in a sample of 118 children and 200 of their parents. We chose this as our primary method of analysis although we also tested for transmission disequilbrium using the Transmission Disequilibrium Test.…”

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Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children

et al. 1999

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Attention deficit hyperactivity disorder (ADHD) is a common disorder of childhood characterized by inattention, excessive motor activity, impulsivity, and distractibility. It is associated with serious disability in children, adolescents and adults. 1 The etiology of the disorder is unknown, but it has a strong genetic component. Pharmacological and biochemical studies have suggested that dopaminergic and noradrenergic systems are involved. 2 Using a sample of affected children and their parents we have found preferential transmission of alleles at polymorphisms at the dopamine transporter (DAT1), RR = 1.2 (1.05-1.37), P = 0.006, re-confirming and extending our previous findings for DAT1 3 (new sample one-tailed P = 0.039); dopamine-␤-hydroxylase (DBH), RR = 1.31 (1.09-1.56), P = 0.0027; and the dopamine D5 receptor (DRD5), RR = 1.67 (1.29-2.15), P = 0.00005. Transmission of the 'associated' alleles at DAT1 and DBH is stronger in familial cases, RR DAT1 = 1.29 (1.04-1.59), RR DBH = 1.49 (1.10-2.00), but for DRD5, transmission is stronger in non-familial cases, RR = 1.59 (1.05-2.42). TDT analysis of complete trios supports the HHRR analysis, with P Ͻ 0.05, for DAT1 P Ͻ 0.005 and DBH and P Ͻ 0.01 for DRD5. Attributable fractions for DAT1, DBH and DRD5 are calculated at 0.08, 0.12 and 0.20 respectively.ADHD affects between 4% and 6% of the school-age population. 4,5 It affects boys two to three times more frequently than girls and leads to significant behavioral problems, impaired family and social relationships and major difficulties in school. Many children with ADHD develop conduct disorder and the long-term outcome is poor. 1 ADHD is familial 6 and twin studies estimate heritability (h 2 ) at 80-90%. [7][8][9] The mode of transmission is unknown, but is likely to be due to many genes, each of small effect. Overall 1st.Deg.Rel is 5-6, 10 suggesting that relative risks at individual loci will be small, and below the resolution of linkage studies. 11 We 3 previously confirmed an association 12 with the 480-bp allele of a VNTR situated in the 3Ј untranslated region of the DAT1 gene. 13 A further replication of this finding is provided by Waldman et al. 14 However, recent work proposes a more complicated neurochemical process including relative hypo-and hyper-dopaminergic function and involving the noradrenergic system. 2 We therefore extended our studies to include other monoamine-related genes.The dopamine transporter gene is a member of a family of Na + and Cl − dependent neurotransmitter transporters containing twelve transmembrane domains. 15 This gene confers all of the pharmacological properties of the rat dopamine re-uptake carrier 16 including the capacity to bind cocaine and other psychostimulant drugs. A 40-bp polymorphic tandem repeat was identified in the 3Ј UTR and was used in the present study. Dopamine-␤-hydroxylase (D␤H) catalyses the conversion of dopamine to noradrenaline. The gene (DBH) is closely linked to the ABO blood group on chromosome 9q34. Enzyme activity in serum or plasma is a stable, hi...

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Cloning of the Human Dopamine D5 Receptor Gene and Identification of a Highly Polymorphic Microsatellite for the DRD5 Locus That Shows Tight Linkage to the Chromosome 4p Reference Marker RAF1P1

Cited by 65 publications

References 0 publications

Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor

Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor

A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder

Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children

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