| Written | 2008-12 | Francesco Di Fabio, Bruce Gottlieb, Lenore K Beitel, Mark Trifiro |
| Cattedra di Chirurgia Generale, Department of Medical, Surgical Sciences, University of Brescia, Brescia, Italy (FDF); Lady Davis Institute for Medical Research-Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada (BG, LKB, MT) |
| Identity |
| Alias (NCBI) | MCR | MGC133092 | MLR | MR |
| HGNC (Hugo) | NR3C2 |
| HGNC Alias symb | MR |
| HGNC Previous name | MLR |
| HGNC Previous name | nuclear receptor subfamily 3, group C, member 2 |
| LocusID (NCBI) | 4306 |
| Atlas_Id | 44262 |
| Location | 4q31.23 [Link to chromosome band 4q31] |
| Location_base_pair | Starts at 148078764 and ends at 148444698 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping NR3C2.png] |
| Local_order | Genes flanking NR3C2 are Rho GTPase activating protein 10 and argininosuccinate synthetase pseudogene 8. |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| ARHGAP10 (4q31.23)::NR3C2 (4q31.23) | NR3C2 (4q31.23)::NR3C2 (4q31.23) | NR3C2 (4q31.23)::SPPL3 (12q24.31) | |
| DNA/RNA |
 | |
| 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. | |
| Description | 10 exons; 363,729 bases DNA. |
| Transcription | Multiple (at least four) mRNA isoforms are generated by alternative transcription or slicing events. Multiple mRNA isoforms are translated into various protein variants. |
| Protein |
| Description | 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. |
| Expression | 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. |
| Localisation | 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. |
| Function | Transcription factor activity, receptor activity, protein binding, sequence-specific DNA binding, steroid binding, steroid hormone receptor activity, metal ion binding, zinc ion binding. |
| Homology | Member of the nuclear hormone receptor family, NR3 subfamily. |
| Mutations |
| Note | 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 |
| Note | |
| Entity | Leukaemia |
| Note | Some of the leukaemic cell lines express both the MR and the amiloride-sensitive sodium channel. |
| Oncogenesis | 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 | Colorectal carcinoma |
| Note | Reduction of MR mRNA expression is an early event in human sporadic carcinoma progression. |
| Oncogenesis | 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 | Cervical carcinoma |
| Note | 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 | Renal cell neoplasms |
| Note | 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 | Lung carcinoma |
| Note | 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 | Breast carcinoma |
| Note | Expression of MR, as detected with immunohistochemistry, appears to be related to ductal differentiation of breast carcinomas. |
| To be noted |
| Several studies investigating the role of aldosterone and MR in cardiovascular risk and target organ damage may offer important hints to understand the potential involvement of MR in cancer development. Under particular investigation are the relationship between MR/aldosterone and cellular growth factor receptors expression (such as EGFR or VEGFR). |
| Bibliography |
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| Underexpression of mineralocorticoid receptor in colorectal carcinomas and association with VEGFR-2 overexpression. |
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| Localization of mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase type II in human breast and its disorders. |
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| Citation |
| This paper should be referenced as such : |
| Di, Fabio F ; Gottlieb, B ; Beitel, LK ; Trifiro, M |
| NR3C2 (nuclear receptor subfamily 3, group C, member 2) |
| Atlas Genet Cytogenet Oncol Haematol. 2009;13(11):858-860. |
| Free journal version : [ pdf ] [ DOI ] |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Thu Jan 20 14:13:22 CET 2022 |
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