Alternative titles; symbols
HGNC Approved Gene Symbol: NR3C2
Cytogenetic location: 4q31.23 Genomic coordinates (GRCh38): 4:148,078,764-148,445,508 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q31.23 | Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy | 605115 | 3 | |
| Pseudohypoaldosteronism type I, autosomal dominant | 177735 | Autosomal dominant | 3 |
Mineralocorticoids, such as aldosterone, are mainly involved in the maintenance of water and salt homeostasis by regulating vectorial sodium transport in tight epithelia. Aldosterone has also been implicated in other physiologic processes, including development of cardiac fibrosis and differentiation of brown adipose tissue. NR3C2, or mineralocorticoid receptor (MR), belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor that mediates the effects of aldosterone on a variety of target tissues, including the distal parts of the nephron, the distal colon, the cardiovascular and central nervous systems, and brown adipose tissue. MR possesses the same affinity for glucocorticoids as for mineralocorticoids, suggesting that it may also function as a high-affinity glucocorticoid receptor (summary by Zennaro et al., 2001).
By low-stringency Southern analysis of placenta DNA using human glucocorticoid receptor (GR, or GCCR; 138040) cDNA as probe, followed by screening human kidney cDNA libraries, Arriza et al. (1987) cloned NR3C2, which they called MR. The deduced 984-amino acid protein has a calculated molecular mass of 107 kD. Like glucocorticoid receptor, mineralocorticoid receptor has an N-terminal cysteine-rich DNA-binding region and a C-terminal steroid-binding domain separated by a putative hinge region. Northern blot analysis of rat tissues detected Mr expression in classic mineralocorticoid target tissues, such as kidney and gut, as well as in brain, pituitary, and heart. It was also highly expressed in hippocampus.
Using Western blot analysis, Alnemri et al. (1991) showed that human MR was expressed in insect cells as 3 proteins with apparent molecular masses of 115, 119, and 125 kD. These proteins were highly phosphorylated. Immunofluorescence analysis showed that MR was primarily cytoplasmic in the absence of aldosterone, and that activation by aldosterone provoked translocation of the receptor to the nucleus. Analytical gel filtration and sucrose gradient ultracentrifugation revealed that MR associated in a complex of 9S to 10S, which was reduced to about 4S following activation by aldosterone.
Zennaro et al. (1995) identified 2 splice variants of MR, called MR-alpha and -beta, that contain alternative first exons. The coding region beginning in exon 2 is identical in MR-alpha and -beta. Using in situ hybridization with exon-specific probes, Zennaro et al. (1997) detected expression of both variants in all typical human MR-expressing cells and tissues analyzed. MR-alpha and -beta were present in distal tubules of kidney, in cardiomyocytes, in enterocytes of colonic mucosa, and in keratinocytes and sweat glands. Zennaro et al. (1997) demonstrated that MR-alpha and -beta were coexpressed in aldosterone target tissues.
Bloem et al. (1995) identified an MR splice variant in both human and rat that contains an additional 12 nucleotides at the 3-prime end of exon 3, resulting in a 4-amino acid insertion in the DNA-binding domain. RT-PCR detected the short and long MR variants in all rat tissues examined and in human white blood cell mRNA. The long transcript was less abundant in all rat tissues except liver, where both transcripts appeared equally expressed.
Using RT-PCR, Zennaro et al. (2001) identified 3 splice variants of MR that were variably expressed in human tissues and cell lines: full-length MR, a variant lacking exon 5, and a variant lacking both exons 5 and 6, which they called MR-delta-5,6. The variant lacking exon 5 encodes a protein lacking part of the N-terminal DNA-binding domain and all of the hinge region. Skipping of both exons 5 and 6 in MR-delta-5,6 introduces a frameshift and a premature stop codon, resulting in a 706-amino acid protein with a calculated molecular mass of 75 kD. MR-delta-5,6 includes the complete N-terminal DNA-binding region of full-length MR, but it has a novel 35-amino acid tail replacing the hinge region and hormone-binding domain.
Zennaro et al. (1995) determined that the human MR gene spans over approximately 400 kb and contains 10 exons. Exons 1-alpha and 1-beta are composed only of 5-prime untranslated sequence and splice into a common translated region. The N-terminal part of the receptor is encoded by exon 2; small exons 3 and 4 encode each of the 2 zinc fingers of the DNA-binding domain. The hormone-binding domain is encoded by exons 5 through 9.
Arriza et al. (1987) mapped the NR3C2 gene to chromosome 4 by testing their cDNA against a panel of rodent-human somatic cell hybrids. To confirm the assignment to chromosome 4, they tested a restricted set of microcell hybrids, each of which carries 1 to 3 human chromosomes. By in situ hybridization using a biotinylated cDNA clone, Morrison et al. (1989, 1990) regionalized the NR3C2 gene to 4q31.1; by the same method, Fan et al. (1989) assigned NR3C2 gene to 4q31.2.
Expression studies by Arriza et al. (1987) demonstrated the ability of MR to bind aldosterone with high affinity and to activate gene transcription in response to aldosterone. MR also showed high affinity for glucocorticoids. Arriza et al. (1987) speculated that, since the circulating level of glucocorticoids is several times higher than those of aldosterone, the primary mineralocorticoid, glucocorticoid activation of MR may be functionally significant.
By assaying human MR overexpressed in insect cells, Alnemri et al. (1991) showed that MR bound aldosterone, cortisol, cortexolone, and progesterone with high affinity. MR bound immobilized DNA even as a large inactive complex, and activation did not increase its DNA-binding capacity.
Zennaro et al. (1995) found that expression of MR-beta was reduced in sweat glands of 2 patients with mineralocorticoid abnormalities, one with Conn syndrome and the other with Liddle syndrome (177200). However, MR expression was not altered in a patient with type I pseudohypoaldosteronism (see 177735).
The hormone-binding domain (HBD) of MR contains 4 cysteine residues, C808, C849, C910, and C942, and Lupo et al. (1998) mutated each of these into serine in an MR construct containing only the DNA-binding domain (DBD), the hinge region, and the HBD. Most of these mutations altered substrate affinity, but not substrate specificity, of the construct. The C849S substitution reduced binding to aldosterone, and the C942S substitution abrogated binding to all substrates tested. The wildtype DBD-hinge-HBD construct showed about 20% of the transcriptional activity of full-length MR in reporter gene assays. The C849S substitution reduced the transcriptional activity of the construct, and the C942S substitution inactivated the construct. Lupo et al. (1998) concluded that C849 and C943 are critical for ligand binding of MR.
Using alanine scanning mutagenesis, Hellal-Levy et al. (2000) studied the role of the residues of the loop connecting H11 and H12 in the activation of the human mineralocorticoid receptor (MR). H950A retained the ligand binding and transcriptional activities of the wildtype receptor and interacted with coactivators. In contrast, F956A had no receptor functions. Aldosterone bound to the mutant MRs (L952A, K953A, V954A, E955A, P957A) with nearly the same affinity as to the wildtype receptor and caused a receptor conformational change in these mutant MRs as it does for the wildtype receptor. The authors proposed that the integrity of the H11-H12 loop is crucial for folding the receptor into a ligand-binding competent state and for establishing the network of contacts that stabilize the active receptor conformation.
Zennaro et al. (2001) showed that in vitro-translated MR-delta-5,6 lacked the ability to bind aldosterone or dexamethasone. MR-delta-5,6 bound DNA and functioned as a ligand-independent transactivator of the consensus glucocorticoid response element (GRE) from the mouse mammary tumor virus promoter. MR-delta-5,6 did not interact with full-length MR, but coexpression of MR-delta-5,6 increased the transactivation potential of full-length MR or GR at high doses of hormone. In addition, MR-delta-5,6 recruited the coactivators SRC1 (NCOA1; 602691), RIP140 (NRIP1; 602490), and TIF1-alpha (TRIM24; 603406), which enhanced its transcriptional activity. Zennaro et al. (2001) concluded that MR-delta-5,6 may modulate corticosteroid effects in target tissues.
Aldosterone enhances angiotensin II (see 106150)-induced PAI1 (173360) expression in vitro. Sawathiparnich et al. (2003) tested the hypothesis that angiotensin II type 1 and aldosterone receptor antagonism interact to decrease PAI1 in humans. Effects of candesartan, spironolactone, or combined candesartan/spironolactone on mean arterial pressure, endocrine, and fibrinolytic variables were measured in 18 normotensive subjects in whom the renin (179820)-angiotensin-aldosterone system was activated by furosemide. This study evidenced an interactive effect of endogenous angiotensin II and aldosterone on PAI1 production in humans.
Shibata et al. (2008) showed that a constitutively active RAC1 (602048) mutant potentiated aldosterone-induced mineralocorticoid receptor nuclear accumulation and transcriptional activity in HEK293 cells transfected with human constructs. In cultured rat podocytes, activated RAC1 facilitated mineralocorticoid receptor nuclear accumulation via p21-activated kinase (PAK; see 602590) phosphorylation. Shibata et al. (2008) found that mice lacking Rho GDP-dissociation inhibitor-alpha (ARHGDIA; 601925) developed progressive renal disease characterized by heavy albuminuria and podocyte damage. These renal changes were associated with increased Rac1 and mineralocorticoid receptor signaling in the kidney without alteration in systemic aldosterone status. Pharmacologic intervention with a Rac-specific small molecule inhibitor diminished mineralocorticoid receptor overactivity and renal damage. Furthermore, mineralocorticoid receptor blockade suppressed albuminuria and histologic changes in Arhgdia -/- mice. Shibata et al. (2008) concluded that RAC1 modulates mineralocorticoid receptor activity, and that activation of the RAC1-mineralocorticoid receptor pathway has a major role in the pathogenesis of renal damage.
Jeong et al. (2009) noted that aldosterone interacts with MR to activate transcription of proinflammatory genes, in addition to activating inflammatory signaling pathways in an MR-independent manner. They showed that aldosterone triggered exocytosis of Weibel-Palade bodies from human aortic endothelial cells, causing the release of proinflammatory mediators. Small interfering RNA directed against MR reduced the effect of aldosterone on exocytosis. Exocytosis also required calcium signaling.
Pseudohypoaldosteronism Type I, Autosomal Dominant
Although studies of Chung et al. (1995) excluded MLR as the site of the mutation causing autosomal recessive pseudohypoaldosteronism type I (PHA1B1; 264350), Geller et al. (1998) presented evidence that the autosomal dominant form of the disorder (PHA1A; 177735) is caused by mutations in the MLR gene. Autosomal dominant or sporadic PHA1 is a milder disease than the autosomal recessive form and remits with age. Among 6 dominant and 7 sporadic PHA1 kindreds, Geller et al. (1998) found no mutations in the epithelial sodium channel (ENaC) genes (600228, 600760) in which mutations have been found in the autosomal recessive form of PHA1. As ENaC activity in the kidney is regulated by aldosterone acting through the mineralocorticoid receptor, Geller et al. (1998) screened the MLR gene for variants and identified heterozygous mutations in 1 sporadic and 4 dominant kindreds. These included 2 frameshift mutations (1 a de novo mutation), 2 premature termination codons, and a splice donor mutation.
In a Japanese patient with sporadic PHA, Arai et al. (2003) found 3 homozygous substitutions in the MR gene that had previously been reported to occur in healthy populations. Luciferase activities induced by MR were significantly lower for each of the 3 substitutions than those for wildtype MR with aldosterone at 3 different concentrations.. Arai et al. (2003) suggested that 2 or more 'functional' polymorphisms, any of which exhibits only slight effects on MR function alone and is incapable of causing PHA, may in the right allelic combination induce the negative salt conservation characteristic of PHA.
Sartorato et al. (2003) analyzed the NR3C2 gene in 14 families with autosomal dominant or sporadic PHA1. They detected 6 heterozygous mutations that differently affected protein structure and function. The authors concluded that NR3C2 mutations are a common feature of autosomal dominant PHA1, being found in 70% of their familial cases. Sartorato et al. (2003) used the numbering of Arriza et al. (1987) to refer to the mutations.
Pujo et al. (2007) identified 22 abnormalities of the NR3C2 gene in 33 patients with type I pseudohypoaldosteronism. Altogether, 68% of the mutations were dominantly transmitted, while 18% were de novo mutations.
Riepe et al. (2006) detected 6 heterozygous NR3C2 mutations in 7 pseudohypoaldosteronism type I (PHA1) patients from 6 unrelated families. Two frameshift mutations, 1131dupT (600983.0008) and 2871dupC (600983.0006) had been reported. They also reported 2 novel nonsense mutations and 2 missense mutations.
Hypertension, Early-Onset, Autosomal Dominant, with Severe Exacerbation in Pregnancy
Geller et al. (2000) screened the mineralocorticoid receptor in 75 patients with early onset of severe hypertension (605115). A 15-year-old boy with severe hypertension, suppressed plasma renin activity, low serum aldosterone, and no other underlying cause of hypertension was heterozygous for a missense mutation, resulting in substitution of a leucine for serine at codon 810 (600983.0005). Of 23 relatives of the proband, 11 were diagnosed with severe hypertension before age 20 years, and the MR S810L mutation precisely cosegregated with early-onset hypertension in this family. This mutation resulted in constitutive MR activity and altered receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists.
Berger et al. (1998) generated MLR-deficient mice by gene targeting. These mice had a normal prenatal development. During the first week of life, the MLR-deficient mice developed symptoms of pseudohypoaldosteronism. They lost weight and eventually died at approximately 10 days after birth from dehydration by renal sodium and water loss. At day 8, MLR -/- mice showed hyperkalemia, hyponatremia, and a strong increase in renin, angiotensin II, and aldosterone plasma concentrations. The fractional renal Na+ excretion was elevated more than 8-fold. The glomerular filtration rate in MLR -/- mice was not different from that in controls. The effect of amiloride on renal Na+ excretion in colonic transepithelial voltage reflected the function of amiloride-sensitive epithelial Na+ channels.
Le Menuet et al. (2001) generated transgenic (TG) mice with the proximal human MR promoter to drive expression of human MR in aldosterone target tissues. Ribonuclease protection analysis revealed human MR expression in mineralocorticoid-sensitive tissues, notably kidney and heart. Histologic analysis showed that enlarged kidneys were associated with renal tubular dilation and cellular vacuolization, the prevalence of which increased with aging. Urinary potassium excretion rates were decreased in the TG mice. Although blood pressure was normal, the TG mice developed mild dilated cardiomyopathy accompanied by a significant heart rate increase and an increase in cardiac ANP (NPPA; 108780), renal and cardiac serum- and glucocorticoid-induced kinase (SGK; 602958), and early growth response-1 (EGR1; 128990).
Berger et al. (2006) conditionally deleted the MR gene in the forebrain of mice and screened them in various learning and exploration tests. Mutant mice showed impaired learning of the water maze task and deficits in measures of working memory on the radial maze due to behavioral perseverance and stereotypy. They showed hyperactive exploration toward novel objects but normal anxiety-like behavior. The behavioral changes were associated with abnormalities of the mossy fiber projection and upregulated glucocorticoid receptor (GCCR; 138040) expression in the hippocampus. Adult mutant mice showed normal basal circadian hypothalamic-pituitary-adrenal axis activity.
In a sporadic case of type I pseudohypoaldosteronism (PHA1A; 177735), Geller et al. (1998) found heterozygosity for a de novo single-bp deletion, introducing a frameshift at codon 335 and resulting in premature termination at codon 337.
In a mother and son with type I pseudohypoaldosteronism (PHA1A; 177735), Geller et al. (1998) found heterozygosity for a 1-bp deletion, introducing a frameshift at codon 459 and resulting in premature termination at codon 474.
In multiple subjects affected with type I pseudohypoaldosteronism (PHA1A; 177735) in each of 2 presumably unrelated families, Geller et al. (1998) found heterozygosity for a C-to-T transition that converted codon 537 from CGA (arg) to TGA (stop).
In affected subjects in a kindred with type I pseudohypoaldosteronism (PHA1A; 177735), Geller et al. (1998) found heterozygosity for a single-bp deletion in the donor splice site following exon 5. The third basepair of the splice donor site was deleted in the mutant allele so that gtagg became gtgg.
Geller et al. (2000) screened the mineralocorticoid receptor in 75 patients with early onset of severe hypertension (605115). In a 15-year-old boy with severe hypertension, a C-to-T substitution, changing codon 810 of the hormone-binding domain from a serine to a leucine, was identified. The ser810-to-leu (S810L) mutation was identified in heterozygous state in 11 family members of this proband who had been diagnosed with severe hypertension before the age of 20 years, resulting in constitutive MR activity and altered receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. This resulted in profound exacerbation of hypertension during 5 pregnancies in 2 affected women in this kindred. Structural and biochemical studies indicated that S810L results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wildtype receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation. The effect of the S810L mutation was to invert the mineralocorticoid receptor from aldosterone-responsive to progesterone-responsive, with development of hypertension during pregnancy. This was the first mendelian form of preeclampsia to be identified. Ordinarily, blood pressure goes down during early stages of pregnancy.
In a sporadic case of type I pseudohypoaldosteronism (PHA1A; 177735), Viemann et al. (2001) found a heterozygous insertion of a cytosine at position 2871 in exon 9. This mutation leads to a frameshift, which results in a nonsense protein from codon 958 and a first stop codon at position 1012.
Riepe et al. (2006) detected this mutation in a patient with PHA1. They showed that the receptor lacked aldosterone-binding and transactivation capabilities because of a major change in receptor conformation.
Tajima et al. (2000) studied the molecular mechanisms of 1 Japanese family with a renal form of pseudohypoaldosteronism type I (PHA1A; 177735). PCR and direct sequencing of the mineralocorticoid receptor gene identified a heterozygous point mutation changing codon 924, leucine (CTG) to CCG (proline) (L924P), in all affected members. In vitro expression studies demonstrated that the L924P mutation results in complete absence of MR function.
In twins and their brother and mother in a family with pseudohypoaldosteronism type I (PHA1A; 177735), Sartorato et al. (2003) found insertion of a thymine at nucleotide position 1345 in exon 2 of the MR gene, resulting in frameshift and premature termination of the receptor at amino acid 378 (E378X).
Riepe et al. (2006) detected this mutation in an Italian family with PHA1A. They referred to the mutation as 1131dupT, with numbering beginning at the A of the initiation codon.
In a family with pseudohypoaldosteronism type I (PHA1A; 177735), Sartorato et al. (2003) found in 2 sibs and their mother a deletion of 8 bp in exon 2 of the MR gene (del8bp537). The frameshift resulted in a truncated protein with 8 novel residues after ser104, followed by a premature stop codon.
In a patient with pseudohypoaldosteronism type I (PHA1A; 177735), Sartorato et al. (2003) found a C-to-A transversion at nucleotide 2157 in exon 4 of the MR gene that caused a cys645-to-ter (C645X) truncation in the second zinc finger of the MR DNA-binding domain. The mutation was apparently sporadic.
In a proband, her mother, and maternal grandfather with pseudohypoaldosteronism type I (PHA1A; 177735), Sartorato et al. (2003) found an A-to-G transition at nucleotide 2549 in exon 5 of the MR gene, changing gln776 to arg (Q776R) in the ligand-binding domain of the mineralocorticoid receptor. Q776R mutant protein displayed only 30% of maximal aldosterone binding.
In 2 brothers and all 4 of their offspring with pseudohypoaldosteronism type I (PHA1A1; 177735), Sartorato et al. (2003) found a G-to-A transition at nucleotide 2119, the last nucleotide of exon 3, that caused substitution of gly633 with arg (G633R). The G633R mutation exhibited reduced maximal transactivation, although its binding characteristics and ED50 of transactivation were comparable with those of wildtype MR.
In a proband and her mother with pseudohypoaldosteronism type I (PHA1A; 177735), Sartorato et al. (2003) found a T-to-C transition at nucleotide 3158 in exon 9 of the MR gene, resulting in a leu-to-pro change at codon 979 (L979P) in the ligand-binding domain. L979P was shown to exert a transdominant-negative effect on wildtype MR activity, and mutant protein demonstrated no aldosterone-binding activity.
In a German patient with a renal form of pseudohypoaldosteronism type I (PHA1A; 177735), Riepe et al. (2003) detected a heterozygous point mutation, 488C-G in exon 2 of the NR3C2 gene, that resulted in substitution of a premature termination codon for serine-163 (S163X). Segregation analysis revealed the same mutation in the patient's father, who had shown no symptoms of PHA. Riepe et al. (2003) sought polymorphisms in the amiloride-sensitive epithelial sodium channel (ENaC; see 600228) as the basis of the phenotypic differences within the family; sequencing revealed identical ENaC haplotypes in the patient and his father, indicating that these polymorphisms could not be responsible for the difference in clinical presentation.
In a Turkish infant with a renal form of pseudohypoaldosteronism type I (PHA1A; 177735), Riepe et al. (2004) detected a heterozygous C-to-T transition at nucleotide 3055 in exon 9 of the NR3C2 gene that caused premature termination of the mineralocorticoid receptor at arginine-947 (R947X). The truncated receptor was free of aldosterone binding. Segregation analysis revealed the identical mutation in the patient's father, who was clinically free of symptoms and showed normal plasma electrolytes and aldosterone urinary metabolites and only slightly elevated plasma renin and aldosterone levels. The authors concluded that their findings supported the hypothesis that PHA1 due to NR3C2 mutations can show incomplete penetrance, although a mild salt loss might have been overlooked in the father's childhood.
In 2 families with autosomal dominant PHA1, unrelated to the family described by Riepe et al. (2004), Fernandes-Rosa et al. (2006) identified the R947X mutation. Different haplotypes segregated with the mutation in each family, suggested that codon 947 is a mutation hotspot.
In the index patient of a 5-generation Swedish family with 15 affected members with autosomal dominant pseudohypoaldosteronism type I (PHA1A; 177735), Nystrom et al. (2004) found a heterozygous T-to-A transversion at nucleotide 1308 in exon 2 of the NR3C1 gene that caused premature termination of the mineralocorticoid receptor at codon 436 (C436X). The mutation was found to segregate with PHA1 in the family. Complete abrogation of the DNA- and hormone-binding domains was predicted in the truncated mutant protein. Interestingly, neuropathy was found in 2 of 5 affected individuals. It was unclear whether the neuropathy was associated with the mutation found.
In a proband and her mother with pseudohypoaldosteronism type I (PHA1A; 177735), Riepe et al. (2006) found a C-to-T transition at nucleotide 2017 in exon 5 of the NR3C1 gene, resulting in premature termination of the protein at arg673 (R673X). The mutation deleted the ligand-binding domain. While plasma aldosterone and renin activity were elevated in the mother, she had no recollection of treatment or hospitalization related to this condition.
In a patient with pseudohypoaldosteronism type I (PHA1A; 177735), Riepe et al. (2006) detected a C-to-T transition at nucleotide 2024 in exon 5 of the NR3C1 gene that caused termination of the protein at ser675 (S675X). The mutation deleted the ligand-binding domain.
In 2 sibs with pseudohypoaldosteronism type I (PHA1A; 177735) and their father, Riepe et al. (2006) detected a C-to-T transition at nucleotide 2453 in exon 6 of the NR3C1 gene, resulting in substitution of leu for ser at codon 181 (S181L). This mutation had been reported by Geller et al. (2006). The S181L mutant showed no aldosterone binding, transcription activation, or translocation to the nucleus. Based on in vitro studies Riepe et al. (2006) hypothesized that substitution of the bulky apolar leucine for serine-818 displaces beta-sheet-1, which severely disturbs the interaction of the receptor with its ligand.
In a patient with pseudohypoaldosteronism type I (PHA1A; 177735) and his mother, Riepe et al. (2006) detected a 2915A-G transition in exon 9 of the NR3C1 gene that resulted in substitution of gly for glu972 (E972G). The novel E972G mutation showed a significantly lower ligand-binding affinity and only 9% of wildtype transcriptional activity caused by major changes in receptor conformation. The mutation was predicted to open the hydrophobic core of the protein and displace helix H10, disturbing the interaction of the receptor with its ligand.
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