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Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits.

ABSTRACT: Because dopamine D(1) receptors (DRD1) influence renal sodium transport and vascular hemodynamics, we examined whether genetic polymorphisms play a role in renal function. We conducted polymorphism discovery across the DRD1 open reading frame and its 5'-UTR and then performed association studies with estimated glomerular filtration rate (eGFR), plasma creatinine (pCr), and fractional excretion of uric acid (FeUA). We used a twin/family group of 428 subjects from 195 families and a replication cohort of 677 patients from the Kaiser health-care organization sampled from the lower percentiles of diastolic blood pressures. Although the coding region lacked common non-synonymous variants, we identified two polymorphisms in the DRD1 5'-UTR (G-94A, A-48G) that occurred with frequencies of 15 and 30%, respectively. In the twin/family study, renal traits were highly heritable, such that DRD1 G-94A significantly associated with eGFR, pCr, and FeUA. Homozygotes for the G-94A minor allele (A/A) exhibited lower eGFR, higher pCr, and lower FeUA. No effects were noted for DRD1 A-48G. Patients in the Kaiser group had similar effects of G-94A on eGFR and pCr. Kidney cells transfected with the -94A variant but not the wild type vectors had increased receptor density. Because the -94A allele is common and may reduce glomerular capillary hydrostatic pressure, G-94A profiling may aid in predicting survival of renal function in patients with progressive renal disease.

SUBMITTER: Fung MM

PROVIDER: S-EPMC2803094 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits.

Fung Maple M MM Rana Brinda K BK Tang Chih-Min CM Shiina Tetsuo T Nievergelt Caroline M CM Rao Fangwen F Salem Rany M RM Waalen Jill J Ziegler Michael G MG Insel Paul A PA O'Connor Daniel T DT

Kidney international 20090812 10

Because dopamine D(1) receptors (DRD1) influence renal sodium transport and vascular hemodynamics, we examined whether genetic polymorphisms play a role in renal function. We conducted polymorphism discovery across the DRD1 open reading frame and its 5'-UTR and then performed association studies with estimated glomerular filtration rate (eGFR), plasma creatinine (pCr), and fractional excretion of uric acid (FeUA). We used a twin/family group of 428 subjects from 195 families and a replication co ...[more]

PMID: 19675531

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Project description:BackgroundExtensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context.MethodsGFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo.ResultsUi-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice.ConclusionsDRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.

Project description:BACKGROUND: The elevation of egg production and the inhibition of incubation behavior are the aims of modern poultry production. Prolactin (PRL) gene is confirmed to be critical for the onset and maintenance of these reproductive behaviors in birds. Through PRL, dopamine D1 receptor (DRD1) was also involved in the regulation of chicken reproductive behavior. However, the genetic effects of this gene on chicken egg production and broodiness have not been studied extensively. The objective of this research was to evaluate the genetic effects of the DRD1 gene on chicken egg production and broodiness traits. RESULTS: In this study, the chicken DRD1 gene was screened for the polymorphisms by cloning and sequencing and 29 variations were identified in 3,342 bp length of this gene. Seven single nucleotide polymorphism (SNPs) among these variations, including a non-synonymous mutation (A+505G, Ser169Gly), were located in the coding region and were chosen to analyze their association with chicken egg production and broodiness traits in 644 Ningdu Sanhuang individuals. Two SNPs, G+123A and C+1107T, were significantly associated with chicken broody frequency (P < 0.05). Significant association was also found between the G+1065A - C+1107T haplotypes and chicken broody frequency (P < 0.05). In addition, the haplotypes of G+123A and T+198C were significantly associated with weight of first egg (EW) (P = 0.03). On the other hand, the distribution of the DRD1 mRNA was observed and the expression difference was compared between broodiness and non-broodiness chickens. The DRD1 mRNA was predominantly expressed in subcutaneous fat and abdominal fat of non-broodiness chicken, and then in heart, kidney, oviduct, glandular stomach, hypothalamus, and pituitary. In subcutaneous fat and abdominal fat, the level of non-broodiness was 26 to 28 times higher than that of broodiness. In pituitary, it was 5-fold higher. In heart, oviduct, and kidney, a 2-3 times decrease from non-broodiness to broodiness was displayed. In glandular stomach and hypothalamus, the level seen in non-broodiness and broodiness was almost the same. CONCLUSION: The polymorphisms of the DRD1 gene and their haplotypes were associated with chicken broody frequency and some egg production traits. The mRNA distribution was significant different between broodiness and non-broodiness chickens.

Dataset Information

Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits.

Publications

Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits.

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