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Mineralocorticoid receptor

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Target id: 626

Nomenclature: Mineralocorticoid receptor

Systematic Nomenclature: NR3C2

Family: 3C. 3-Ketosteroid receptors

Contents:

Gene and Protein Information Click here for help
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 984 4q31 NR3C2 nuclear receptor subfamily 3 group C member 2 2
Mouse 978 8 36.34 cM Nr3c2 nuclear receptor subfamily 3, group C, member 2 3
Rat 981 19q11 Nr3c2 nuclear receptor subfamily 3, group C, member 2 79
Previous and Unofficial Names Click here for help
aldosterone receptor | Type I glucocorticoid receptor | MCR | MLR | MR | nuclear receptor subfamily 3
Database Links Click here for help
Specialist databases
Transcriptomine NR3C2&foldChange=1.6&direction=down, NR3C2&foldChange=1.75&direction=up
Other databases
Alphafold P08235 (Hs), Q8VII8 (Mm), P22199 (Rn)
CATH/Gene3D 3.30.50.10
ChEMBL Target CHEMBL1994 (Hs), CHEMBL3507 (Rn)
DrugBank Target P08235 (Hs)
Ensembl Gene ENSG00000151623 (Hs), ENSMUSG00000031618 (Mm), ENSRNOG00000034007 (Rn)
Entrez Gene 4306 (Hs), 110784 (Mm), 25672 (Rn)
Human Protein Atlas ENSG00000151623 (Hs)
KEGG Gene hsa:4306 (Hs), mmu:110784 (Mm), rno:25672 (Rn)
OMIM 600983 (Hs)
Orphanet ORPHA123920 (Hs)
Pharos P08235 (Hs)
RefSeq Nucleotide NM_000901 (Hs), NM_001083906 (Mm), NM_013131 (Rn)
RefSeq Protein NP_000892 (Hs), NP_001159576 (Hs), NP_001077375 (Mm), NP_037263 (Rn)
SynPHARM 6580 (in complex with aldosterone)
6578 (in complex with deoxycorticosterone)
6583 (in complex with dexamethasone)
6579 (in complex with progesterone)
78981 (in complex with spironolactone)
UniProtKB P08235 (Hs), Q8VII8 (Mm), P22199 (Rn)
Wikipedia NR3C2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  DNA-binding Domain (Mineralocorticoid Receptor)
PDB Id:  4TNT
Resolution:  2.39Å
Species:  Human
References:  49
Image of receptor 3D structure from RCSB PDB
Description:  Mineralocorticoid receptor ligand binding domain with bound aldosterone.
PDB Id:  2AA2
Ligand:  aldosterone   This ligand is endogenous
Resolution:  1.95Å
Species:  Human
References:  9
Natural/Endogenous Ligands Click here for help
aldosterone
corticosterone
cortisol
deoxycorticosterone
progesterone
Rank order of potency (Human)
corticosterone, cortisol, aldosterone, progesterone  [95]

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]aldosterone Small molecule or natural product Ligand is labelled Ligand is radioactive Ligand has a PDB structure Rn Agonist 9.4 – 9.5 pKd 42,105
⤷ pKd 9.4 – 9.5 (Kd 4x10-10 – 3x10-10 M) [42,105]
prednisolone Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 7.4 pKi 22
⤷ pKi 7.4 (Ki 3.7x10-8 M) [22]
budesonide Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 7.8 pEC50 47
⤷ pEC50 7.8 (EC50 1.4x10-8 M) [47]
fluticasone propionate Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 6.8 pEC50 47
⤷ pEC50 6.8 (EC50 1.49x10-7 M) [47]
deoxycorticosterone Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 11.0 pIC50 95
⤷ pIC50 11.0 [95]
fludrocortisone Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Agonist 9.9 pIC50 95
⤷ pIC50 9.9 [95]
aldosterone Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 9.8 – 10.0 pIC50 46,95
⤷ pIC50 9.8 – 10.0 [46,95]
cortisol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 9.8 – 9.9 pIC50 46,95
⤷ pIC50 9.8 – 9.9 [46,95]
dexamethasone Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 9.0 pIC50 46,95
⤷ pIC50 9.0 [46,95]
prednisolone Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 8.0 pIC50 91
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [91]
AZD9567 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist <4.4 pIC50 91
⤷ pIC50 <4.4 (IC50 >3.8x10-5 M) [91]
corticosterone Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist - -
⤷
benzodrocortisone Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist - - 31
⤷ [31]
View species-specific agonist tables
Antagonists Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
spironolactone Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Antagonist 8.6 pKi 4
⤷ pKi 8.6 (Ki 2.32x10-9 M) [4]
apararenone Small molecule or natural product Hs Antagonist 7.0 pKi 51
⤷ pKi 7.0 (Ki 1x10-7 M) [51]
Description: Binding to hMR
eplerenone Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Antagonist 6.9 pKi 4
⤷ pKi 6.9 (Ki 1.24x10-7 M) [4]
AZD9977 Small molecule or natural product Ligand has a PDB structure Hs Antagonist <5.0 pKi 43
⤷ pKi <5.0 (Ki >1x10-5 M) [43]
Description: Binding affinity to hMR.
progesterone Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Antagonist 11.0 pIC50 95
⤷ pIC50 11.0 [95]
esaxerenone Small molecule or natural product Approved drug Ligand has a PDB structure Hs Antagonist 8.6 pIC50 53,81
⤷ pIC50 8.6 (IC50 2.4x10-9 M) [53,81]
ocedurenone Small molecule or natural product Hs Antagonist 8.6 pIC50 21
⤷ pIC50 8.6 (IC50 2.7x10-9 M) [21]
PF-03882845 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.0 pIC50 20
⤷ pIC50 8.0 (IC50 9.2x10-9 M) [20]
finerenone Small molecule or natural product Approved drug Hs Antagonist 7.7 pIC50 17
⤷ pIC50 7.7 (IC50 1.8x10-8 M) [17]
nimodipine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 6.8 pIC50 30
⤷ pIC50 6.8 (IC50 1.6x10-7 M) inhibition of aldosterone-induced luciferase activity in a reporter system driven by the mineralocorticoid receptor ligand binding domain [30]
onapristone Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.3 pIC50 126
⤷ pIC50 6.3 (IC50 4.7x10-7 M) [126]
drospirenone Small molecule or natural product Approved drug Primary target of this compound Hs Antagonist - - 82
⤷ [82]
ZK112993 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷
RU28318 Small molecule or natural product Hs Antagonist - -
⤷
Antagonist Comments
Several other antagonists are in various stages of development and are reviewed by Collin et al., 2014 [25].
DNA Binding Click here for help
Structure:  Homodimer, Heterodimer
HRE core sequence:  ACAAGANNNTGTTCT
Response element:  GRE, Half site, Palindrome
DNA Binding Comments
MR and GR can heterodimerize. HRE sequence has variations that contribute to gene-specific regulation.

Additional response elements are described in Ziera et al., 2009 [128].

Analysis of the cistromes for the human and rat MRs is reported by Le Billan et al. (2015) [61] and van Weert et al. (2017) [114] respectively.
Co-binding Partners Click here for help
Name Interaction Effect Reference
Rac1 100
HMGD Physical, Functional DNA binding 11,116
Glucocorticoid receptor Physical, Functional DNA binding 63,66-68,75,111
HSP90 complex Physical, Functional Cellular localization 34,38-40,84
Epidermal growth factor receptor 44
Co-binding Partners Comments
MR interacts with other members of the HSP90 complex including, hsp70, p23, the FκBPs and the cyclopholins [16,85-86].
Main Co-regulators Click here for help
Name Activity Specific Ligand dependent AF-2 dependent Comments References
PPARGC1A Co-activator No Yes No Strong MR coactivator and highly expressed in brown adipocytes. 37
PPARGC1A Co-activator Yes Yes No Elongation factor that directly interacts with the N-terminal domain of MR and acts as a potent coactivator; strongly represses GR transactivation and has no effect on AR or PR activity. 78
NCOA1 Co-activator No Yes Yes First member of a large coactivator family (SRC1, 2, 3). DNA-bound steroid receptors interact with SRC-1 which initiate sequential recruitment of SWI/SNF chromatin remodeling complexes, histone-methyltransferase proteins CARM1/PRMT1 and histone acetylases such as CBP/p300-pCAF.

Sites of interaction with the MR: AF-2; AF-1 by SRC-1e isoform. Recruits histone acetylation complex to initiate transcription; weak intrinsic histone acetyltransferase activity.		 50,76,118,125
NCOA2 Co-activator - No Yes Sites of interaction with the MR: AF-1, AF-2. Enhances transactivation. 37,48,118
EP300 Co-activator - No Yes Sites of interaction with the MR: AF-1, AF-2. Exerts histone acetyltransferase activity; recruits RNA polymerase II to target gene promoter. 37
PPARGC1A Co-activator - No Yes Sites of interaction with the MR: AF-2. Recruits histone acetyltransferase complex; facilitates binding of NR to transcription initiation complex. 50,55
ELL Co-activator - No - Sites of interaction with the MR: AF-1b. RNA polymerase II elongation factor; prevents premature arrest and transient pausing of polymerase II. 78
CASP8AP2 Co-activator - No - Sites of interaction with the MR: AF-1. Regulates cell apoptosis. 72
FAF1 Co-activator - No - Sites of interaction with the MR: AF-1. Regulates cell apoptosis. 72
NRIP1 Co-activator - No - Sites of interaction with the MR: N-terminal domain 125
NCOR2 Co-repressor No No Yes Recruited to antagonist bound steroid receptors followed by recruitment of histone deacetylase proteins (HDAC).

Sites of interaction with the MR: ligand binding domain.		 118
NCOR1 Co-repressor No No Yes Recruited to antagonist bound steroid receptors followed by recruitment of histone deacetylase proteins (HDAC).

Sites of interaction with the MR: ligand binding domain.		 118
NFYC Co-repressor - No - Sites of interaction with the MR: AF-1. Inhibits aldosterone-induced MR N-C interaction. 65
PIAS1 Co-repressor Yes Yes No PIAS1, a SUMO-E3 ligase, inhibits transactivation by MR and AR but not that by GR. Sites of interaction with the MR: N-terminal domain, possibly ligand binding domain. Exact mechanism of repressive action unclear. 109
DAXX Co-repressor - No - Sites of interaction with the MR: N-terminal domain. Regulates cell apoptosis; represses MR transactivation in some cell lines. 72
UBE2I Co-activator - No - Sites of interaction with the MR: N-terminal domain. SUMO E2-conjugating enzyme; forms coactivation complex with SRC-1. 122
TRIM24 Co-activator - No - Sites of interaction with the MR: N-terminal domain. Transcriptional coactivator / corepressor. 125
RACK1 Co-activator No Yes - The mechanisms of the direct interaction has not been shown. The coactivation is dependent on phosphorylation of RACK1 by PKCβ. 59
GEMIN4 Co-repressor Yes Yes Yes Cell-specific repression of MR signalling. 120
TESMIN Co-activator Yes Yes Yes Sites of interaction with the MR: AF-2. Aldosterone-specific. 93
Main Co-regulators Comments
A publication describing RHA as a MR co-regulator (Kitagawa et al., 2002) has been retracted [54,69].
XRCC6, EEF1A1 and SSRP1 are non-specific, ligand-dependent coregulators that confer tissue specific regulation [121].
Main Target Genes Click here for help
Name Species Effect Technique Comments References
Sgk1 Rat Activated the focal induction of serum and glucocorticoid-regulated kinase 1 (SGK1) is in the distal nephron and colon 7,14,101
Fxyd4 Rat Activated Fxyd4 or the chanel-inducing factor (Chif) is a member of the FXYD membrane protein family associated with Na+K+ATPase. 13
K-Ras2A None Activated Northern blot analysis, real-time RT-PCR Using the Xenopus laevis kidney-derived A6 cell line, the K-ras transcript of the K-ras gene was identified as aldosterone induced. 15,106
Mmp12 Mouse Activated PCR Validated as apart of myeloid cell inflammatory response to MR activation. 74,99
Per1 Mouse Activated Microarray, Northern blot 45
Per2 Mouse Activated Microarray, Northern blot 45
Ctgf Mouse Activated Microarray, Northern blot 45
Cnksr3/CNKSR3 Mouse Activated ChIP NB: mouse AND human. Validated as part of the regulatory complex associated with ENaC 103,128
Fkbp5 Rat Activated qRT-PCR of endogenous target gene, Western blotting 80
WNK1 Human Activated Semiquantitative RT-PCR 70
ICAM1 Human Activated qRT-PCR, immunoblotting 19
Edn1 Rat Activated Northern blot analysis, real-time RT-PCR 119
Serpine1 Rat Activated RT-PCR 123
Ndrg2 Rat Activated RT-PCR 12
SCNN1A Human Activated ENaC (SCNN1A) is transcriptionally regulated by aldosterone as an early event in distal colon but not in the kidney. However, aldosterone does increase ENaC number and activity on kidney epithelial cell surface. 1,102
GILZ/Tsc22d3 Mouse Activated Serial analysis of gene expression (SAGE) Subsequently has been validated as a functionally relevant MR regulated gene in several tissues and species. 87,92,104
Main Target Genes Comments
K-Ras2 gene is activated by MR in Xenopus [115]. A small G protein and a proto-oncogene was found to be rapidly induced by aldosterone, enhances Na+ current. Other genes activated include the following: Na+, K+ ATPase α1 and β1 [56-57,57].

In addition to the genes listed above, regulation of L-type Ca2+ channel [62], osteogenic genes including alkaline phosphatase (ALP) and bone morphogenetic protein-2 (BMP2) [52], the RNA polymerase II elongation factor ELL (eleven-nineteen lysine-rich leukemia; [78]), the ubiquitin-specific protease Usp2-45 [33], and Sgk1, Fkbp5, Rasl12, Tns1 and Tsc22d3 (Gilz) which were validated as direct target genes of MR by quantitative RT-qPCR and ChIP-qPCR in a study using a murine distal convoluted tubular epithelial cell-line [112].
Tissue Distribution Click here for help
Brain, heart, kidney, colon, aorta, hippocampus, hypothalamus, adrenal fasciculata.
Species:  Human
Technique:  Northern, Q-PCR, in situ, Western, immunohistology
References:  27,58
Tissue Distribution Comments
Classic aldosterone-sensitive tissues include epithelia with high electrical resistance, such as the distal parts of the nephron, the surface epithelium of the distal colon, and salivary and sweat gland ducts. More recently, other MR-expressing cells have been identified, either epithelial, as in epidermal keratinocytes, or nonepithelial, as in the neurons of the central nervous system, the cardiac myocytes, and the endothelial and smooth muscle cells of the vasculature (large vessels). Similar patterns of expression are also seen in rodents.

There is also extensive documentation of MR expression in renal and cardiac cell types (reviewed in Odermatt and Kratschmar, 2012 [73]).

In addition to those human tissues listed above, there are now many more documented in the literature, including female reproductive tissues (ovary, breast), auditory and retinal tissues, inflammatory cells, particularly the monocyte/macrophage lineage, the rest of the gastrointestinal tract although highest levels are undoubtedly in the distal colon.

The MR is co-expressed with 11βHSD2 in a small number of nuclei in the nucleus of the solitary tract (NTS); in these nuclei the role of the MR is to regulate salt appetite in response to aldosterone and therefore sodium balance. They occupy a subregion of the NTS with a diminished blood brain barrier which may afford exposure to circulating aldosterone. These neurons express the angiotensin receptor and MR activation appears to interact synergistically with AngII to promote salt appetite [41,88].

Expression datasets are available from these referenes: [45,83,92,107].
Functional Assays Click here for help
Renal clearance
Species:  Mouse
Tissue:  Urine
Response measured:  Ion levels
References:  5
Colonic transepithelial Na+ reabsorption
Species:  Mouse
Tissue:  Colon, in vivo
Response measured:  Colonic transepithelial potential difference is measured in vivo by a double-barreled flexible polyethylene tube that could be perfused by Ringer-type solution ± amiloride (3 µmol/liter). This tube was inserted into the rectum at a length of 7 mm. The electrical potential of this tube is measured by a high input resistance differential amplifier and was referenced to an Ag/AgCl electrode that was inserted under the skin
References:  5,102
Physiological Consequences of Altering Gene Expression Click here for help
Homozygous MR-deficient mice:- show normal prenatal development, during week one they developed symptoms of pseudohypoaldosteronism, lost weight and died at around day 10 after birth from dehydration by renal sodium and water loss. At day 8, -/- mice showed hyperkalemia, hyponatremia, and a strong increase in renin, angiotensin II, and aldosterone plasma concentrations.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells
References:  5
A conditional knock-down model by expressing solely in the heart an antisense mRNA directed against the murine MR. Within 2-3 mo, mice developed severe heart failure and cardiac fibrosis in the absence of hypertension or chronic hyperaldosteronism.
Species:  Mouse
Tissue:  Heart
Technique:  Antisense oligonucleotide
References:  3
Gene targeting has been used to generate mice in which serine is substituted for cysteine at codon 603 in the MR; this mutation precludes DNA binding. These mice when bred to homozygosity show the same features as observed previously for mice null for the MR gene. This mouse model demonstrates that DNA binding is essential for the epithelial MR response.
Species:  Mouse
Tissue: 
Technique:  Homologous recombination.
References:  23
Forebrain/CNS knockout: Impaired learning and memory, altered level of anxiety. Neural mossy-fibre abnormalities, increased GR levels in the brain.
Species:  Mouse
Tissue:  Neurons.
Technique:  CamKII-Cre
References:  6
Renal nephron knockout: Survive with severe PHA-1, die on Na+-deficient diet. Reduced renal ENaCα & Na+/Cl- co-transporter levels.
Species:  Mouse
Tissue:  Nephron
Technique:  Pax8-Cre
References:  18,110
Renal tubule knockout: Survival to adult, elevated RAAS activity. Na+/water loss on a low sodium diet
Species:  Mouse
Tissue:  CD and CNT
Technique:  Aqp2-Cre
References:  94
Vascular smooth muscle cells (VSMC) knockout: impaired blood pressure regulation in ageing, altered vascular tone. Induced VSM α5-integrin, aldosterone/salt
Species:  Mouse
Tissue:  Smooth muscle
Technique:  SMA-CRE/ERT2
References:  64
Endothelial cell knockout: No ddeoxycorticosterone/salt-mediated cardiac fibrosis, no macrophage recruitment (Tie2-Cre). Obesity-induced dysfunction blunted inflammation (VE-Cad-Cre)
Species:  Mouse
Tissue: 
Technique:  Tie2-Cre, VE-Cad-Cre
References:  90,98
Cardiomyocyte knockout: Improved cardiac remodelling post-infarct (MLC2a-Cre). Protected from deoxycorticosterone/salt-mediated cardiac fibrosis (MLC2v-Cre).
Species:  Mouse
Tissue: 
Technique:  MLC2a-Cre, MLC2v-Cre
References:  35,71,89
Skin knockout: mice were resistant to age-induced epidermal atrophy but had reductions in dermal thickness, collagen deposition and SMAD2 and 3 activity.
Species:  Mouse
Tissue:  Epidermis
Technique:  K5-Cre
References:  8
Physiological Consequences of Altering Gene Expression Comments
There are now a series of tissue-specific MR knockouts. The physiology of these at baseline is limited although in a pathophysiology context the effects are profound (see [24]).
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr3c2tm2Gsc|Tg(Camk2a-cre)2Gsc Nr3c2tm2Gsc/Nr3c2tm2Gsc,Tg(Camk2a-cre)2Gsc/0
involves: 129P2/OlaHsd * C57BL/6 * FVB/N		 MGI:2181425  MGI:99459  MP:0002761 abnormal hippocampal mossy fiber morphology PMID: 16368758 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0001765 abnormal ion homeostasis PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0002829 abnormal juxtaglomerular apparatus PMID: 9689096 
Nr3c2tm1Krst|Tg(Camk2a-cre)2Gsc Nr3c2tm1Krst/Nr3c2tm1Krst,Tg(Camk2a-cre)2Gsc/?
involves: FVB/N		 MGI:2181425  MGI:99459  MP:0004753 abnormal miniature excitatory postsynaptic currents PMID: 16361444 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0005325 abnormal renal glomerulus morphology PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0010109 abnormal renal sodium reabsorption PMID: 9689096 
Nr3c2tm2Gsc|Tg(Camk2a-cre)2Gsc Nr3c2tm2Gsc/Nr3c2tm2Gsc,Tg(Camk2a-cre)2Gsc/0
involves: 129P2/OlaHsd * C57BL/6 * FVB/N		 MGI:2181425  MGI:99459  MP:0003461 abnormal response to novel object PMID: 16368758 
Nr3c2tm2Gsc|Tg(Camk2a-cre)2Gsc Nr3c2tm2Gsc/Nr3c2tm2Gsc,Tg(Camk2a-cre)2Gsc/0
involves: 129P2/OlaHsd * C57BL/6 * FVB/N		 MGI:2181425  MGI:99459  MP:0001463 abnormal spatial learning PMID: 16368758 
Nr3c2tm2Gsc|Tg(Camk2a-cre)2Gsc Nr3c2tm2Gsc/Nr3c2tm2Gsc,Tg(Camk2a-cre)2Gsc/0
involves: 129P2/OlaHsd * C57BL/6 * FVB/N		 MGI:2181425  MGI:99459  MP:0008428 abnormal spatial working memory PMID: 16368758 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0005634 decreased circulating sodium level PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0001429 dehydration PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0010128 hypovolemia PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0002666 increased circulating aldosterone level PMID: 9689096 
Nr3c2+|Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2+
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0002666 increased circulating aldosterone level PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0005627 increased circulating potassium level PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0003352 increased circulating renin level PMID: 9689096 
Nr3c2+|Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2+
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0003352 increased circulating renin level PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0002608 increased hematocrit PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0005582 increased renin activity PMID: 9689096 
Nr3c2+|Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2+
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0005582 increased renin activity PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0006316 increased urine sodium level PMID: 9689096 
Nr3c2+|Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2+
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0006316 increased urine sodium level PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0006275 natriuresis PMID: 9689096 
Nr3c2+|Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2+
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0006275 natriuresis PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0002082 postnatal lethality PMID: 9689096 
Nr3c2tm2.1Gsc Nr3c2tm2.1Gsc/Nr3c2tm2.1Gsc
involves: C57BL/6		 MGI:99459  MP:0002082 postnatal lethality PMID: 16368758 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0001263 weight loss PMID: 9689096 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Pseudohyperaldosteronism type 2
Synonyms: Hypertension, early-onset, autosomal dominant, with severe exacerbation in pregnancy [OMIM: 605115]
OMIM: 605115
Orphanet: ORPHA88660
Comments:  Alteration at the receptor level: S819L mutant gains function.
References:  97,108
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human S819L Gain of function
Disease:  Renal pseudohypoaldosteronism type 1
Synonyms: Pseudohypoaldosteronism, type 1, autosomal dominant; PHA1A [OMIM: 177735]
OMIM: 177735
Orphanet: ORPHA171871
Role:  A mild form of mineralocorticoid resistance involving only one allele. This is distinct from the severe autosomal recessive form of PHA1 which involves mutations in the epithelial sodium channel genes. Recent studies have addressed the broader consequences of haploinsufficiency that characterises PHA1 with MR mutations for the pituitary adrenal axis (Walker et al. 2014) and for the cardiovascular system (Escoubet et al., 2013).
Comments:  Alteration at the receptor level: G633R, Q776R, L924P and L979P mutants lose activity.
References:  32,97,108,117,124
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human G633R Loss of function 97
Missense Human Q776R Loss of function 97
Missense Human L924P Loss of function 108
Missense Human L979P Loss of function 97
Biologically Significant Variants Click here for help
Type:  Polymorphism
Species:  Human
Description:  A G/C polymorphism at position -2 of the human MR mRNA 5’-untranslated region has been associated with activation of the RAAS and regulation of blood pressure. The G allele was associated with both lower MR levels and together with lower transcriptional activity, and whereas the GG genotype correlated with higher plasma aldosterone levels and higher blood pressure in males. G allele carriers exhibit a greater cortisol response to stress and altered performance strategies in learning tests [2].
Nucleotide change:  .-2G>C
Global MAF (%):  0.45
References:  60,113
Type:  Polymorphism
Species:  Human
Description:  A 538A>G mutation in exon 2 causes an Ile180Val missense change in the N-terminal domain of the human MR.In healthy human subjects, responses to psychosocial stress showed cortisol levels and heart rate were enhanced for the G/Val allele
Amino acid change:  Ile180Val
Nucleotide change:  538A>G
References:  29
Type:  Truncation
Species:  Human
Description:  A Gln919STOP, maternally inherited mutation in the human MR ligand-binding domain has been identified in three brothers with autism. Gln919 lies in helix 10, and although Gln 919 does not lie in the ligand-binding pocket, the truncation alters portions of the pocket and of AF-2. How this mutation affects MR signalling is unknown. Other human MR variants have been reported to be associated with autism, a condition which is characterised by altered levels of stress and responses to anxiety
Amino acid change:  Gln919STOP
References:  26,28,96
Type:  Species variant
Species:  Human
Description:  Threonine at position 870 in helix 8 of the LBD in the human MR is conserved across terrestrial vertebrates (except in rodents where there is a serine at the equivalent position). In contrast a leucine occurs at the equivalent position in the fish MR enabling it to form a stabilizing bond with a leucine in helix 1 of the LBD. This evolutionary switch, leucine to threonine/serine is responsible for progesterone (and spironolactone) being an agonist in fish and an antagonist in terrestrial vertebrates.
Amino acid change:  Leu870>Thr/Ser
References:  36
Type:  Alternative promoters and splicing
Species:  Human
Description:  mineralocorticoid receptor isoform 1 (MR-A) is the full length transcript
Protein accession:  NP_000892
References:  77
Type:  Alternative promoters and splicing
Species:  Human
Description:  mineralocorticoid receptor isoform 2 (MR-B) is an N-terminus truncated transcript of hMR
Protein accession:  NP_001159576
References:  77
Biologically Significant Variant Comments
Human mineralocorticoid receptor isoform 1 (MR-A) has higher transactivation activity than MR-B. Other splicing variants include: A 12-bp insertion at the 3' of exon 3 results in a four-residue addition in between the two zinc fingers of the DBD and no difference in activity compared to the wild-type receptor; a 10-bp deletion in rat MR results truncated LBD at residue 807, unresponsive to aldosterone, and no interference with wild-tpe receptor function; exon-skipping in human generates mutants lacking exon 5 or both exons 5 and 6 which binds to DNA and modulate wild-type receptor activity in a ligand-independent manner [10,125,127].

References

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