NR3C2 (nuclear receptor subfamily 3, group C, member 2)

2008-12-01   Francesco Di Fabio , Bruce Gottlieb , Lenore K Beitel , Mark Trifiro 




Atlas Image
Schematic representation of human mineralocorticoid receptor (MR/NR3C2) structure. The human MR/NR3C2 gene is composed of 10 exons. The first 2 exons (1alpha and 1beta) are untranslated. However, alternative transcription of these exons can give rise to 2 RNA isoforms. The subsequent eight exons encode for the entire MR protein. MR/NR3C2 has three major functional domains: a modulating N-terminal domain (NTD), a central DNA-binding domain (DBD) and a C-terminal steroid ligand-binding domain (LBD). Exon 2 encodes for most of the NTD, exons 3 and 4 encode for each of the two zinc fingers of the DBD and the remaining five exons encode the LBD. AUG: start codon; UGA: stop codon.


10 exons; 363,729 bases DNA.


Multiple (at least four) mRNA isoforms are generated by alternative transcription or slicing events. Multiple mRNA isoforms are translated into various protein variants.



984 amino acids. Like all member of the nuclear receptor superfamily, the MR has 3 major domains: an N-terminal domain (NTD), a DNA-binding domain (DBD) and a ligand-binding domain (LBD). The NTD (602 amino acids) is composed of several functional domains (AF-1a, a central domain and AF-1b) that recruit various coregulators responsible for selectively modulating the transcriptional activity of MR. The DBD (66 amino acids) recognizes specific target DNA sequences or hormone response elements. The LBD (251 amino acids) is a multifunctional domain allowing selective hormone binding. The LBD includes the ligand-dependent AF-2 functional domain, which undergoes a rearrangement upon ligand binding.


Ubiquitous. MR expression has been reported in the kidney, colon, breast, salivary glands, sweat glands, liver, cardiomyocytes, endothelial cells, lung, central nervous system (hippocampus, hypothalamus), ocular tissues (retina, iris-ciliary body), adipose tissues (white and brown), inner ear, skin, placenta, uterus, ovaries and testis.


Cytoplasm, nucleus, endoplasmic reticulum membrane, peripheral membrane: cytoplasmic and nuclear in the absence of ligand; nuclear after ligand-binding. When bound to 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2), it is found associated with the endoplasmic reticulum membrane.


Transcription factor activity, receptor activity, protein binding, sequence-specific DNA binding, steroid binding, steroid hormone receptor activity, metal ion binding, zinc ion binding.


Member of the nuclear hormone receptor family, NR3 subfamily.



Loss-of-function mutations. About 50 distinct mutations in the human MR are known to be responsible for pseudohypoaldosteronism type 1 (PHA1). This is an autosomal genetic disorder caused by loss-of-function mutations. The mutations reported are missense, nonsense, frameshift, splice site mutations and deletions. PHA1 is characterized by salt wasting due to loss-of-function of the MR in the target organs. There are 2 forms of PHA1: the autosomal dominant form, which may be severe at birth, but symptoms remit with age, and the recessive form, which manifests with more severe symptoms persisting into adulthood.
Gain-of-function mutations. Only one mutation, to date, is known to result in a gain-of-function of MR. The single mutation S810L in the LBD leads to a constant MR activation. The inheritance is autosomal dominant. The disease is characterized by the onset of severe hypertension before the age of 20, with severe exacerbation in pregnancy.

Implicated in

Entity name
Some of the leukaemic cell lines express both the MR and the amiloride-sensitive sodium channel.
Some leukemic cell lines respond to mineralocorticoid steroids by an altered growth response that may possibly be linked to apoptosis. The altered sodium flux due to the induction of the amiloride-sensitive sodium channel by mineralocorticoids may cause uncontrolled cell proliferation in cancer.
Entity name
Colorectal carcinoma
Reduction of MR mRNA expression is an early event in human sporadic carcinoma progression.
A significant inverse association between MR and vascular endothelial growth factor receptor-2 (VEGFR-2) expression at the mRNA level has been detected in human colorectal carcinoma, suggesting a potential tumor-suppressive function for MR. The degree of MR underexpression may have a role in the pro-angiogenic switch of colorectal carcinoma.
Entity name
Cervical carcinoma
In a study of gene expression profiles in squamous cell cervical carcinoma, NR3C2 was observed to be significantly downregulated, which would suggest that it should be considered as a new putative cervical cancer-related gene.
Entity name
Renal cell neoplasms
Using immunohistochemistry, expression of both MR and its related enzyme 11 beta-HSD2 was detected in chromophobe renal cell carcinoma and in oncocytomas. No staining was detected in clear cell renal cell carcinomas. MR and 11 beta-HSD2 may be considered specific immunohistochemical markers of the distal nephron and its related neoplasms (chromophobe renal cell carcinoma and oncocytoma).
Entity name
Lung carcinoma
It has been reported that MR and 11 beta-HSD2 seem to be expressed only in adenocarcinomas or in the adenocarcinomatous component of adenosquamous carcinomas. No MR or 11 beta-HSD2 expression was detected in squamous cell carcinomas. MR and 11 beta-HSD2 immunoreactivity have been significantly correlated with the grade of differentiation of adenocarcinomas. Patterns of MR and 11 beta-HSD2 expression as detected with immunohistochemistry may reflect the cellular origin and differentiation status of primary human lung carcinoma, and may serve as a marker of differentiation.
Entity name
Breast carcinoma
Expression of MR, as detected with immunohistochemistry, appears to be related to ductal differentiation of breast carcinomas.


Pubmed IDLast YearTitleAuthors
30377031987Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor.Arriza JL et al
150638302004Aldosterone signaling modifies capillary formation by human bone marrow endothelial cells.Chen W et al
175043822007Gene expression profiles in squamous cell cervical carcinoma using array-based comparative genomic hybridization analysis.Choi YW et al
177033412007Underexpression of mineralocorticoid receptor in colorectal carcinomas and association with VEGFR-2 overexpression.Di Fabio F et al
172936892007Aldosterone, mineralocorticoid receptors, and vascular inflammation.Fiebeler A et al
182494282008Nongenotropic aldosterone effects and the EGFR: interaction and biological relevance.Grossmann C et al
129392632003Aldosterone stimulates epidermal growth factor receptor expression.Krug AW et al
168471462006Aldosterone impairs bone marrow-derived progenitor cell formation.Marumo T et al
108659752000Demonstration of the mineralocorticoid hormone receptor and action in human leukemic cell lines.Mirshahi M et al
172853012007Is the vascular endothelium under the control of aldosterone? Facts and hypothesis.Oberleithner H et al
129437272003Dissecting mineralocorticoid receptor structure and function.Rogerson FM et al
92166571997Localization of mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase type II in human breast and its disorders.Sasano H et al
107696752000Expression of 11 beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor in primary lung carcinomas.Suzuki S et al
181749202007The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology.Viengchareun S et al
184085922008Mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type II expression in renal cell neoplasms: a tissue microarray and quantitative RT-PCR study.Yakirevich E et al
76731271995Human mineralocorticoid receptor genomic structure and identification of expressed isoforms.Zennaro MC et al

Other Information

Locus ID:

NCBI: 4306
MIM: 600983
HGNC: 7979
Ensembl: ENSG00000151623


dbSNP: 4306
ClinVar: 4306
TCGA: ENSG00000151623


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Aldosterone-regulated sodium reabsorptionKEGGko04960
Aldosterone-regulated sodium reabsorptionKEGGhsa04960
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Nuclear Receptor transcription pathwayREACTOMER-HSA-383280

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
157184972005Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells.100
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
184676302008Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion.78
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
224070822012Mineralocorticoid receptor Iso/Val (rs5522) genotype moderates the association between previous childhood emotional neglect and amygdala reactivity.56
159398172005Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias.49
162758822005Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: a pilot study.49
260154492015Low-Dose Mineralocorticoid Receptor Blockade Prevents Western Diet-Induced Arterial Stiffening in Female Mice.49
217239142012Mineralocorticoid receptors in vascular function and disease.46
242066622013Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia.42


Francesco Di Fabio ; Bruce Gottlieb ; Lenore K Beitel ; Mark Trifiro

NR3C2 (nuclear receptor subfamily 3, group C, member 2)

Atlas Genet Cytogenet Oncol Haematol. 2008-12-01

Online version: