Mineralocorticoid receptor genetics: A scoping review

Abstract

The concept of the mineralocorticoid receptor (MR) has evolved to be recognized as a key regulator of blood pressure homeostasis and multisystem physiology. Beyond its classical roles in renal sodium and water balance, MR activity influences cardiovascular, metabolic, and neurological processes, among others. Advancing our understanding of MR is essential for: (1) Improving pharmacological MR modulation; (2) Optimizing experimental and translational models; and (3) Enhancing the clinical data interpretation. Although substantial progress has been made in elucidating MR molecular biology, knowledge regarding its genetic remains limited. Considering the potential impact of genetic variants on MR structure and function, this review focuses on the current evidence surrounding MR genetics. To date, 460 germline variants of the MR gene have been reported, primarily associated with two phenotypes: (1) Autosomal dominant early-onset hypertension exacerbated during pregnancy; and (2) Autosomal dominant pseudohypoaldosteronism type-I. Therefore, genetics provides a framework for connecting molecular alterations of MR with clinical phenotypes, deepening our understanding of interindividual variability and enabling the development of personalized therapeutic strategies.

Key Words: Mineralocorticoid receptor; Genetics; Nuclear receptor subfamily 3 gene; Genotype; Phenotype

Core Tip: The mineralocorticoid receptor (MR) has emerged as a multifaceted regulator extending beyond electrolyte and blood pressure control to roles in cardiovascular, renal, metabolic, and neural physiology. In addition, MR is expressed in various tissues and organs in humans. However, the genetic dimension of MR function remains underexplored, and the genotype-phenotype correlation is only known for a few MR gene mutations. The genetics of the MR determine its functionality; therefore, a better understanding of it can be the basis of a personalized medicine approach.

INTRODUCTION

In recent years, the mineralocorticoid receptor (MR) has gone from being considered a secondary member of the steroid hormone receptor (SR) family to being recognized as a critical regulator of both physiological and pathological processes[1]. Beyond its classical role in maintaining blood pressure (BP) and extracellular fluid balance, MR participates in complex mechanisms across multiple organs and systems, particularly the renal, cardiovascular, metabolic, and central nervous systems[1].

This expanded understanding reflects a shift from viewing MR solely as an effector of salt and water homeostasis toward recognizing its influence in diverse disease pathways[1]. A deeper comprehension of MR structure and function is fundamental for improving the pharmacological modulation of MR activity, optimizing experimental models, and enhancing the interpretation of clinical data[1].

Despite advances in structural and functional knowledge, the genetic basis of MR biology remains insufficiently characterized. Given the potential impact of genetic variants on receptor conformation and downstream signaling, this review focuses on the genetic aspects of the MR and the nuclear receptor subfamily 3 (NR3C2) gene.

METHODOLOGY

We performed a non-systematic literature search in July 2025 and subsequently updated it. The search was conducted in the MEDLINE, EMBASE, Scopus, Cochrane, and Google Scholar databases using the following terms: [(“mineralocorticoid receptor”) and (“NR3C2 gene”) and (“genetics”)]. All authors agreed on the key articles selected for each topic, and a narrative review of the literature was performed.

General description of the MR

The MR belongs to the SR subgroup of the nuclear receptor superfamily, which also includes the glucocorticoid (GR), progesterone (PR), estrogen, and androgen (AR) receptors[1]. These receptors typically reside in the cytoplasm in an inactive state and function as ligand-activated transcription factors[1].

While MR shares structural similarities with GR, it also exhibits distinctive molecular and functional features that define its specific biological actions[1,2]. The receptor operates as a transcriptional regulator that binds steroid ligands, primarily aldosterone, and modulates gene expression to maintain ionic balance and influence tissue remodeling, inflammation, and metabolism[1,2].

PHYSIOLOGICAL AND PATHOLOGICAL RELEVANCE OF THE MR

In classical epithelial tissues such as the distal nephron, colon, and sweat and salivary glands, aldosterone-activated MR increases sodium and water reabsorption while promoting potassium secretion[1,3]. These actions are essential for BP regulation and the maintenance of extracellular volume[1,3].

MR is also expressed in a wide range of non-epithelial tissues[4-7], including the heart[6], vessels[5,7], adipose tissue[3], immune cells[3], and brain[4], illustrating the receptor’s extensive physiological reach (Tables 1, 2, 3, 4, 5, and 6). In these sites, MR influences vascular tone, cardiac remodeling, adipocyte differentiation, immune activation, and neuronal stress responses[3-7]. In macrophages, MR signaling promotes pro-inflammatory phenotypes that contribute to atherosclerosis and metabolic dysfunction[8].

Table 1 Renal expression of mineralocorticoid receptor.

Organ	Specie	Cellular location	Functional role
Kidney[12,13]	Human	Distal convoluted tubules and cortical collecting ducts	Aldosterone-dependent transepithelial sodium transport
Kidney[14]	Rat	Mesangial cells	Cell proliferation and micromechanical properties
Kidney[15]	Rat	Mesangial cells	Reactive oxygen species induced by aldosterone
Kidney[16]	Rat	Podocytes	Induction of oxidative stress

Table 2 Epithelial expression of mineralocorticoid receptor.

Organ	Specie	Cellular location	Functional role
Colon[17-19]	Rat, human, chicken	Enterocyte	Transepithelial Na+ and water transport
Airway[20]	Rat	Trachea to bronchioles	ND
Salivary glands[21]	Rat	Parotid	ND
Sweat glands[22]	Human	Duct epithelial cells	Na+ and K+ sweat composition and prevents excessive salt loss during heat acclimatization
Skin[22]	Human	Keratinocytes, hair follicle	ND
Skin[23]	Mouse	Keratinocytes	Restrains keratinocyte proliferation and fine-tunes differentiation to maintain epidermal balance
Skin[24]	Mouse	Keratinocytes	Keratinocyte-specific anti-inflammatory action, by inhibiting NF-κB and STAT3 pathways
Skin[25]	Mouse	Keratinocytes	Normal keratinocyte motility and dermal remodeling during wound repair

ND: Not described.

Table 3 Ear and blood expression of mineralocorticoid receptor.

Organ	Specie	Cellular location	Functional role
Inner ear[26]	Rat	Marginal cells of the stria vascularis and spiral ganglion neurons	Regulates endolymph homeostasis by controlling Na+/K+-ATPase activity
Inner ear[27,28]	Guinea pig	Lateral wall of the cochlea basal turn and the ampullae of the semicircular canals	ND
Inner ear[29]	Mouse	Ampulla epithelial cells of semicircular canal	Expressed functional MR and 11β-HSD2; promoted Na+ absorption and K+ secretion through the IsK/KvLQT1 channel
Blood[30-33]	Human	Mononuclear leukocytes	Intracellular Na+/K+ balance
			Induces oxidative stress (↑ p22phox); and upregulates PAI-1 expression
			Induces trained immunity

ND: Not described; MR: Mineralocorticoid receptor; PAI-1: Plasminogen activator inhibitor-1.

Table 4 Central nervous system expression of mineralocorticoid receptor.

Organ	Specie	Cellular location	Functional role
CNS[34-37]	Rat	Hippocampus: Pyramidal neurons of CA1-CA4; granule cells of dentate gyrus	Increases neuronal excitability, facilitating action potential firing
CNS[38]	Mouse	Hippocampus: Pyramidal neurons of CA1-CA4; granule cells of dentate gyrus	Increases glutamate release, strengthening synaptic communication
CNS[39,40]	Mouse	Hippocampus: Pyramidal neurons of CA1-CA4; granule cells of dentate gyrus	Lower anxiety and regulation of the stress response
			Long-term survival and maintenance of mature granule neurons
CNS[41,42]	Rat	Hippocampus: Pyramidal neurons of CA1-CA4; granule cells of dentate gyrus	Inhibition progenitor proliferation
			Synaptic plasticity: Hippocampal long-term potentiation, memory formation, particularly under stress conditions
CNS[34-36]	Rat	Hypothalamus: Parvocellular and magnocellular neurons of PVN and ARC	ND

ARC: Arcuate nucleus; CA: Cornu ammonis; CNS: Central nervous system; ND: Not described; PVN: Paraventricular nucleus.

Table 5 Heart and cardiovascular system expression of mineralocorticoid receptor.

Organ	Specie	Cellular location	Functional role
Heart[43-45]	Rat	Myocytes	Induces cardiomyocyte hypertrophy
Heart[46-48]	Mouse	Myocytes	Ventricular contractile dysfunction
			Increases ROS at and mitochondrial myocardial level, through the overexpression of NADPH oxidase
			Cardiac fibrosis and remodeling
			Apoptosis
Heart, blood vessels[49,50]	Rabbit	Myocytes; endothelial and vascular smooth muscle cells	Promotes endothelial dysfunction and oxidative stress in atherosclerosis
Heart, blood vessels[51]	Rat	Myocytes; endothelial and vascular smooth muscle cells	Promotes vascular smooth muscle cells proliferation

ROS: Reactive oxygen species.

Table 6 Adipose and ocular expression of mineralocorticoid receptor.

Organ	Specie	Cellular location	Functional role
Adipose tissues[52-54]	Mouse	White adipocytes	Proadipogenic, promoting the differentiation of preadipocytes into mature fat cells
Adipose tissues[55-57]	Mouse	Brown adipocytes	Promotes differentiation and down-regulates UCP1 and UCP3 expression, contributing to the regulation of cellular energy expenditure
Retina[58-60]	Rat	Müller glial cells	Regulates Na+, K+ and water channel expression (ENaC-α, Kir4.1, AQP4)
Retina[58-60]	Rat/human	Choroid (vascular endothelium)	Choroidal vascular permeability and vasodilation by KCa23 channel regulation
Iris-ciliary body[61]	Rabbit	ND	ND

AQP: Aquaporin; ENaC: Epithelial sodium channel; Kir: Inwardly rectifying potassium channel; ND: Not described; UCP: Uncoupling protein.

Persistent MR activation has been linked to hypertension, chronic heart failure, renal injury, vascular remodeling, obesity, insulin resistance, and certain neuropsychiatric conditions[5,6,9-11].

Table 1 describes renal MR expression[12-16]; Table 2 summarizes epithelial MR expression[17-25]; Table 3 reports MR expression in the ear and blood[26-33]; Table 4 presents central nervous system MR expression[34-42]; Table 5 describes MR expression in the heart and cardiovascular system[43-51]; and Table 6 shows MR expression in adipose and ocular tissues[51-61].

In summary, MR is indispensable not only for electrolyte and fluid homeostasis, but also as a pivotal mediator of cardiovascular, renal, metabolic, and neural pathophysiology.

Gene structure of the MR (NR3C2 gene): The NR3C2 gene (approved symbol: NR3C2, Group C, Member 2; OMIM: 600983) encodes the MR protein (OMIM^®). It spans approximately 450 kb and is organized into ten exons: Two untranslated (1α and 1β) at the 5′ end, and eight coding exons that produce a 984-amino-acid (aa) protein[62,63].

This exon distribution mirrors the modular structure of the MR: Exon 2 encodes most of the N-terminal domain (NTD), exons 3-4 encode the zinc fingers of the DNA-binding domain (DBD), and exons 5-9 encode the ligand-binding domain (LBD) (OMIM^®).

This genomic arrangement supports the structural and functional modularity typical of nuclear receptors and underlies the receptor’s ability to integrate transcriptional and regulatory functions[64].

Two alternative promoters and alternative splicing events yield several transcript variants, although these are less abundant than the full-length isoform (OMIM^®). These variants can either potentiate MR signaling[65] or act as dominant-negative regulators[66].

Figure 1 provides a schematic overview of the NR3C2 gene and its relationship with the MR protein’s functional domains and post-translational modifications.

Figure 1 Schematic representation of the human mineralocorticoid receptor. DBD: DNA-binding domain; LBD: Ligand-binding domain; NTD: N-terminal domain.

The start codon (AUG) of the NR3C2 gene is located at the beginning of exon 2, and the stop codon is in exon 9. Alternative transcription and splicing give rise to multiple MR isoforms. The receptor contains distinct functional domains: N-terminal activation functions (AF-1a and AF-1b), a central DBD, and a C-terminal LBD with activation function 2 (AF-2). Nuclear localization signals (NLS0, NLS1, NLS2) and a nuclear export signal are indicated. Specific residues undergo post-translational modifications, including phosphorylation, sumoylation, acetylation, and ubiquitylation (OMIM^®).

Gene mapping: The NR3C2 gene is located on chromosome 4q31.23 (GRCh38: 4: 148,078,764-148,445,322; NCBI). It was first mapped to chromosome 4 in 1987 by Arriza et al[67] using human-rodent somatic cell hybrids. Subsequent studies by Morrison et al[62] and Fan et al[68] refined its localization to 4q31.1 and 4q31.2 using in situ hybridization with biotinylated cDNA probes.

MR molecular and protein structure: The MR has the canonical tripartite domain organization shared by steroid receptors[1,64,69]: (1) An NTD; (2) A central DBD; and (3) A C-terminal LBD connected by a hinge region (OMIM^®).

The MR is evolutionarily conserved, with the DBD showing 97% identity between zebrafish and human receptors, while the LBD and NTD exhibit 77% and 33% identity, respectively[70].

NTD

MR has the longest NTD among SR family members (602 amino acids). Its sequence is highly variable between receptor types (< 15% identity) but is highly conserved across species for a given receptor (> 50% homology), suggesting crucial functional significance[64]. Its structure is intrinsically disordered and shaped by protein-protein interactions (PPI) rather than primary sequence[1].

The NTD contains two activation function 1 (AF-1) domains, AF-1a (residues 1-167) and AF-1b (residues 445-602), along with a central regulatory region (residues 163-437) that mediates ligand-independent transactivation or repression[71]. This region interacts with various co-regulators, fine-tuning MR transcriptional activity and contributing to mineralocorticoid specificity[2]. Post-translational modifications of the NTD, including phosphorylation, sumoylation, and acetylation, further regulate its activity in a cell-type-specific manner[72].

DBD

The DBD (66 aa, encoded by exons 3-4 of NR3C2) is responsible for recognizing specific hormone response elements in target DNA. It shares approximately 94% identity with the GR-DBD and > 90% with PR and AR[64].

The DBD contains two perpendicular α-helices coordinated by zinc ions. The first zinc finger includes the P-box (Gly621-Ser-Val625), which binds the minor groove of DNA. The second zinc finger includes the D-box (Ala640-Gly-Arg-Asn-Asp645), facilitating receptor dimerization[64]. MR can form heterodimers with other SRs, notably GR and AR[73], suggesting cross-regulation at the transcriptional level[64].

LBD

The LBD (251 aa) is a complex and multifunctional region that governs ligand selectivity and receptor activation. It is approximately 55% homologous across SRs and highly conserved among species (80%-97%)[64].

Structurally, it consists of 11 α-helices and four antiparallel β-strands that form a three-layer helical sandwich[64]. Crystallographic studies have identified key residues involved in ligand recognition: Gln776 (helix H3) and Arg817 (helix H5) interact with the 3-ketone group of aldosterone, Asn770 (H3) stabilizes the 18-hydroxyl group, residue 848 (H7) determines specificity between MR and GR, and residues 820-844 contribute to aldosterone selectivity[74-76]. Met852 modulates the binding of anti-mineralocorticoid spirolactones[77]. Comparative structural analyses suggest that MR closely resembles the ancestral steroid receptor, implying evolutionary conservation of aldosterone binding even before the hormone’s appearance[78,79].

Two notable evolutionary residues are Ser949 (deleted in most GRs) and His950 (present in Old World primate MR but replaced by glutamine in lower vertebrates), both considered critical divergence points in MR evolution[64].

Historical perspective on MR functional genetics: The molecular characterization of the MR has evolved substantially since its initial description. In 1987, Arriza et al[67] first demonstrated the receptor’s high-affinity binding to aldosterone and its capacity to activate gene transcription, also noting its unexpected high affinity for GRs. They proposed that because circulating GR concentrations exceed those of aldosterone, GR-mediated MR activation could have physiological significance (OMIM^®).

Subsequent studies by Alnemri et al[80] confirmed that MR binds aldosterone, cortisol, cortexolone, and PR with high affinity (OMIM^®). In 1995, Zennaro et al[81] observed reduced MR-β expression in the sweat glands of patients with Conn and Liddle syndromes, whereas receptor expression appeared unaltered in a case of pseudohypoaldosteronism type I (OMIM^®).

Lupo et al[82] examined the functional role of four cysteine residues (C808, C849, C910, C942) through site-directed mutagenesis. They reported that C849S reduced MR affinity for aldosterone and C942S abolished ligand binding entirely, identifying both residues as critical for receptor activation (OMIM^®).

Two studies by Hellal-Levy et al[83,84] explored the structural relevance of the H11-H12 Loop within the LBD. Mutation H950A preserved receptor function, while F956A disrupted ligand binding and transcriptional activity, demonstrating that this loop is essential for proper folding and stabilization of the active MR conformation (OMIM^®).

Further work by Zennaro et al[65] revealed that the MR-Δ5,6 splice variant lacks aldosterone and dexamethasone binding capacity, supporting the importance of full-length structural integrity for functionality (OMIM^®).

Later studies extended these findings to signal transduction. Sawathiparnich et al[85] showed an interactive effect between endogenous angiotensin II and aldosterone on PAI-1 production (OMIM^®). Shibata et al[86] identified Rac1 GTPase as a modulator of MR activity, implicating Rac1-MR cross-talk in renal injury pathogenesis (OMIM^®). Finally, Jeong et al[87] demonstrated that aldosterone can also activate endothelial inflammatory pathways in an MR-independent manner, broadening the scope of MR-related signaling (OMIM^®).

Aldosterone-MR agonism

Aldosterone, a steroid hormone of the mineralocorticoid family, is the principal endogenous ligand of the MR. It regulates BP and fluid–electrolyte balance[88,89]. Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex by aldosterone synthase (encoded by the CYP11B2 gene), under the regulation of extracellular potassium, adrenocorticotropin, and the renin-angiotensin system[90-92]. Cholesterol serves as the precursor, undergoing conversion to pregnenolone and subsequently to 11-deoxycorticosterone before final oxidation to aldosterone[93-95].

Once synthesized, aldosterone diffuses into target cells, binds cytoplasmic MR, and the complex translocates to the nucleus, where it modulates transcription of genes such as SGK1. This induces epithelial sodium channel activation, leading to sodium and water reabsorption, thereby sustaining extracellular volume homeostasis[96,97].

Ligand dissociation kinetics are a key determinant of MR activity, influencing receptor stability, cofactor recruitment, and transcriptional strength[83,84].

Figure 2 illustrates the principal features of aldosterone-MR interaction and transcriptional activation.

Figure 2  Main aspects of aldosterone-mineralocorticoid receptor binding.

MR agonism and antagonism

In addition to mineralocorticoids like aldosterone and deoxycorticosterone, GRs such as cortisol can bind MR as agonists[98]. Despite similar binding affinities, these ligands elicit distinct transcriptional profiles due to differences in receptor stabilization and cofactor interactions[83].

Under physiological conditions, circulating cortisol levels far exceed those of aldosterone[99]. Specificity of MR activation in aldosterone-sensitive tissues is maintained by pre-receptor enzymatic control via the 11β-hydroxysteroid dehydrogenase (11β-HSD) system. 11β-HSD1 is a bidirectional NADPH-dependent enzyme. 11β-HSD2 is an NAD⁺-dependent dehydrogenase that inactivates cortisol to cortisone[99]. In classical aldosterone target tissues such as the distal nephron and colon, 11β-HSD2 prevents inappropriate MR activation by GRs, thereby enforcing aldosterone selectivity[100]. 11β-HSD2 deficiency leads to apparent mineralocorticoid excess syndrome, characterized by hypertension and hypokalemia (OMIM^®).

Conversely, 11β-HSD2 is absent in non-epithelial tissues (e.g., heart, brain, adipose), where MR may act primarily as a high-affinity GR receptor[2]. Additional layers of ligand selectivity include differences in dissociation rates, conformational shifts influencing coregulator binding, and ligand-specific stabilization of MR complexes[2,101].

PR, another high-affinity endogenous ligand, functions as a competitive MR antagonist[67]. The switch between agonism and antagonism is determined by residue Thr870 within the LBD[102]. Notably, a pathogenic NR3C2 variant substituting leucine 810 with serine converts PR from an antagonist to an agonist, producing severe early-onset hypertension despite low plasma aldosterone concentrations[102].

GENETIC RATIONALE FOR STUDYING THE MR

A genetic approach is essential to understand how alterations in the MR contribute to disease[1,2]. Pathogenic variants in the NR3C2 gene clearly illustrate this relationship: Loss-of-function mutations cause renal pseudohypoaldosteronism type I, whereas gain-of-function mutations have been reported in familial forms of mineralocorticoid hypertension exacerbated during pregnancy[103,104]. Beyond these rare monogenic syndromes, common single-nucleotide polymorphisms in NR3C2 have been identified in the general population (OMIM^®). Although such variants do not independently cause overt salt-wasting or hypertension, they modulate salt sensitivity, BP variability, stress responsiveness, and predisposition to mood and cognitive disorders[101]. Structural and functional studies have shown that MR activity depends on the conformational integrity of its NTD, DBD, and LBD (OMIM^®)[105,106]. Variants that alter these regions can modify ligand affinity, cofactor interaction, and transcriptional selectivity[105,106]. Therefore, the study of NR3C2 genetics offers a unique framework to link molecular receptor alterations with clinical phenotypes, helping to explain interindividual variability and paving the way for personalized therapeutic strategies.

MR protein interactions

Even in the absence of a ligand, MR remains functionally connected to several proteins that influence its stability, localization, and transcriptional potential. In the cytoplasm, chaperones such as heat shock proteins (HSP70, HSP90) and immunophilins maintain the receptor in a ligand-receptive conformation[106,107]. Actin participates in nuclear translocation upon receptor activation[108].

Inside the nucleus, MR activity is shaped by the dynamic recruitment of coactivators and corepressors that either enhance or suppress transcriptional output[109]. Table 7[107-127] summarizes the major protein partners of MR and their functional relevance.

Table 7 Interactions of mineralocorticoid receptors in non-aldosterone-bound states.

Protein name	Type	Cellular compartment	Functional role
Hsp90	Chaperone	Cytoplasm	Maintaining MR in an appropriate conformation for ligand binding[107]
Hsp70, Hsp40, Hip(p48)	Chaperone and co-chaperone	Cytoplasm	Stabilize unliganded MR and assist in early complex assembly before Hsp90 recruitment[108-111]
Hop (p60), p23	Co-chaperone	Cytoplasm	Link Hsp70 and Hsp90 during MR complex assembly and stabilize the receptor-chaperone complex[108-111]
BAG-1	Co-chaperone (Hsp70-interacting protein)	Cytoplasm	Modulates MR transcriptional activity[112,113]
FKBP51, FKBP52, PP5	Immunophilins/TPR co-chaperones	Cytoplasm	Regulate receptor transport: FKBP51 impairs nuclear translocation; FKBP52 and PP5 facilitate dynein/dynactin-mediated retrograde transport toward the nucleus[108,111,114]
CyP40	Immunophilin	Cytoplasm and nucleus	TPR-domain co-chaperone that associates with HSP90 complexes; contributes to receptor-HSP90 assembly and may modulate receptor function through regulation of HSP90 ATPase activity[108,111,115]
XAP2/ARA9, WISp39	Immunophilin-like co-chaperones	Cytoplasm	Stabilization and assembly of the HSP90-MR complex[111]
Actin	Chaperone	Cytoplasm	Ligand-dependent nuclear translocation[109]
SRC-1, SRC-2, PGC1-α	Co-regulators (common co- activators)	Nucleus	Interact with LBD and RNA Pol II; enhance transcription through LxxLL motifs[116-119]
CBP/p300	Co-regulator (activator)	Nucleus	Interacts NTD and LBD, induces chromatin remodeling and histone acetylation[118-120]
ELL	Co-regulator (activator)	Nucleus	Potentiates MR activity while repressing GR[121]
HDAC3–4, HDAC5	Co-regulators (modulators)	Nucleus	Modulate MR acetylation and transcriptional activity[122]
RNA Helicase A	Co-regulator (activator)	Nucleus	Recruits CBP and enhances aldosterone-dependent MR transcription[123]
NCoR, SMRT, DAXX	Co-regulators (repressors)	Nucleus	Bind MR and repress its transcriptional function[118,124,125]
PIAS1	Co-regulator (repressor)	Nucleus	SUMOylates MR, repressing its transcriptional activity[71,121]
Rac1 (small GTPase)	Signal transducer	Cytoplasm	Activates MR in a ligand-independent manner (notably in kidney and heart)[87,126]
CHIP	E3 ubiquitin ligase	Cytoplasm	Promotes MR polyubiquitination and proteasomal degradation[127]

MR: Mineralocorticoid receptor; DBD: DNA-binding domain; LBD: Ligand-binding domain; NTD: N-terminal domain; GR: Glucocorticoid; CBP: CREB-binding protein; TPR: Tetratricopeptide repeat.

Gene-phenotype relationships

Two main human phenotypes have been correlated with NR3C2 variants that cause either gain or loss of MR function: (1) Hypertension, early-onset, autosomal dominant, exacerbated during pregnancy (MIM: 605115); and (2) Pseudohypoaldosteronism type I, autosomal dominant (MIM: 177735) (OMIM^®). To date, 460 germline NR3C2 variants have been reported, while no somatic variants have been described. Figure 3 provides a quantitative overview of currently documented NR3C2 variants in OMIM^®. Missense variants constitute the largest group and are distributed across all major functional domains, with prominent clustering in the DBD and LBD, highlighting these regions as mutational hotspots with high functional sensitivity (OMIM^®). Genetic variants affecting the DBD frequently impair DNA recognition and transcriptional regulation of mineralocorticoid-responsive genes, whereas mutations in the LBD often disrupt aldosterone binding, receptor stability, or interactions with transcriptional cofactors. Several LBD variants can alter ligand specificity or receptor activation thresholds, potentially contributing to variable clinical expressivity. In contrast, alterations in the NTD, which harbors the main transactivation function, are more heterogeneous but have been associated with altered transcriptional potency and dysregulated PPIs (OMIM^®).

Figure 3 Genetic variants of the NR3C2 gene currently reported in OMIM^®. A: Germline classification; B: Molecular consequence; C: Variation type; D: Variation size; E: Variation length.

To date, the VarSome platform (https://doi.org/10.1093/bioinformatics/bty897) describes 215 variants of uncertain significance (VUS), 70 pathogenic and probably pathogenic variants, and 68 benign and probably benign variants in NR3C2.

CONCLUSION

The MR is widely expressed across multiple tissues and organ systems, where it participates in diverse physiological and pathological processes. Despite this broad distribution, genotype-phenotype correlations in humans remain limited, currently defined only for rare syndromes resulting from NR3C2 variants that either enhance or abolish mineralocorticoid activity.

Further research into MR genetics is warranted to uncover: (1) New pathways involved in receptor activation; (2) Disease mechanisms associated with NR3C2 variants; and (3) Novel therapeutic implications of MR agonism and antagonism.

Genetic studies provide a unique lens through which to link molecular alterations of the MR to clinical phenotypes, deepening our understanding of interindividual variability and offering valuable perspectives for precision and personalized medicine.

Although loss-of-function NR3C2 genetic variants classically underlie AD pseudohypoaldosteronism type 1, increasing evidence supports broader genotype-phenotype correlations extending beyond this canonical presentation. Hypomorphic variants, regulatory-region polymorphisms, and selected missense changes have been associated with milder salt-wasting phenotypes, late-onset manifestations, or isolated biochemical abnormalities. Conversely, rare gain-of-function variants have been implicated in MR overactivity, contributing to low-renin hypertension in specific contexts.

Integration of curated clinical databases such as ClinVar with population-level resources like gnomAD reveals that a substantial proportion of reported NR3C2 variants are currently classified as VUS. Notably, several of these affect highly conserved residues within the DBD or LBD and show extremely low allele frequencies, suggesting potential pathogenic relevance that warrants functional validation.

Collectively, these observations indicate that the pathogenic landscape of NR3C2 extends beyond classical truncating mutations and encompasses a continuum of functional effects, which may contribute to phenotypic variability, disease penetrance, and interindividual differences in mineralocorticoid sensitivity.

Despite significant progress in the molecular characterization of NR3C2, several important knowledge gaps remain. Most of the current genetic evidence derives from rare monogenic disorders, particularly AD pseudohypoaldosteronism type 1, which represent only a small fraction of the clinical spectrum associated with MR dysfunction. In contrast, the contribution of common and rare genetic variants to prevalent cardiometabolic conditions, such as hypertension, heart failure, and chronic kidney disease, remains poorly understood. Moreover, the polygenic MR-related phenotypes, including potential gene-gene and gene-environment interactions, has been only marginally explored. Emerging genomic technologies are poised to transform this field. Next-generation sequencing enables comprehensive identification of rare coding and regulatory variants across diverse populations, while large-scale genome-wide association studies may uncover common risk alleles that modulate MR signaling in complex diseases. In parallel, CRISPR-based functional screens provide an unprecedented opportunity to systematically interrogate the biological impact of NR3C2 variants, bridging the gap between genetic discovery and mechanistic understanding. Such approaches will be essential to refine variant classification, particularly for the growing number of VUS.

ACKNOWLEDGEMENTS

This work is part of the research line titled “Proyecto: Semillero de Investigación – Proteinuria en trasplante renal” (approved by Resolution No. 23/25, Instituto Universitario Italiano de Rosario). The authors thank the IUNIR Research Institute (ININVI) for its collaboration in the editing and preparation of this manuscript.