Pseudohypoaldosteronism

Summary

Pseudohypoaldosteronism (MONDO:0018638) is a disease with 4 cohort genes and 5 clinical trials. Top therapeutic interventions include enalapril and sodium polystyrene sulfonate.

At a glance

• Cohort genes: 4
• ClinVar variants: 3
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoaldosteronism
Mondo ID	MONDO:0018638
MeSH	D011546
Orphanet	444916
DOID	DOID:4479
NCIT	C85034
SNOMED CT	77098009
UMLS	C0033805
MedGen	18721
GARD	0021861
Is cancer (heuristic)	no

Data availability: 3 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubular transport disease › pseudohypoaldosteronism

Related subtypes (8): Fanconi renotubular syndrome, renal tubular acidosis, Liddle syndrome, familial renal glucosuria, renal hypomagnesemia 3, Gitelman syndrome, Bartter syndrome, Dent disease

Subtypes (2): transient pseudohypoaldosteronism, inherited pseudohypoaldosteronism

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
252501	NM_000901.5(NR3C2):c.1409C>A (p.Ser470Ter)	NR3C2	Pathogenic	criteria provided, single submitter
988230	NM_001038.6(SCNN1A):c.574del (p.Arg192fs)	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
997080	GRCh37/hg19 4q31.23(chr4:148911418-149103259)	ARHGAP10	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCNN1A	Orphanet:130	Brugada syndrome
SCNN1A	Orphanet:171876	Generalized pseudohypoaldosteronism type 1
SCNN1A	Orphanet:526	Liddle syndrome
SCNN1A	Orphanet:60033	Idiopathic bronchiectasis
NR3C2	Orphanet:171871	Renal pseudohypoaldosteronism type 1

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCNN1A	HGNC:10599	ENSG00000111319	P37088	Epithelial sodium channel subunit alpha	clinvar
ARHGAP21	HGNC:23725	ENSG00000107863	Q5T5U3	Rho GTPase-activating protein 21	clinvar
ARHGAP10	HGNC:26099	ENSG00000071205	A1A4S6	Rho GTPase-activating protein 10	clinvar
NR3C2	HGNC:7979	ENSG00000151623	P08235	Mineralocorticoid receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCNN1A	Epithelial sodium channel subunit alpha	This is one of the three pore-forming subunits of the heterotrimeric epithelial sodium channel (ENaC), a critical regulator of sodium balance and fluid homeostasis.
ARHGAP21	Rho GTPase-activating protein 21	Functions as a GTPase-activating protein (GAP) for RHOA and CDC42.
ARHGAP10	Rho GTPase-activating protein 10	GTPase-activating protein that catalyzes the conversion of active GTP-bound Rho GTPases to their inactive GDP-bound form, thus suppressing various Rho GTPase-mediated cellular processes.
NR3C2	Mineralocorticoid receptor	Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	96.5×	0.028
Scaffold/PPI	2	8.6×	0.028
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCNN1A	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS
ARHGAP21	Scaffold/PPI	no		RhoGAP_dom, PDZ, PH_domain
ARHGAP10	Scaffold/PPI	no		RhoGAP_dom, SH3_domain, PH_domain
NR3C2	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Znf_NHR/GATA

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	1
nasal cavity epithelium	1
right uterine tube	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
lower esophagus	1
lower esophagus muscularis layer	1
mucosa of stomach	1
colonic mucosa	1
endothelial cell	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCNN1A	283	broad	marker	nasal cavity epithelium, metanephros cortex, right uterine tube
ARHGAP21	225	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ARHGAP10	202	ubiquitous	marker	mucosa of stomach, lower esophagus muscularis layer, lower esophagus
NR3C2	277	broad	marker	endothelial cell, colonic mucosa, mucosa of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NR3C2	2,188
ARHGAP21	1,768
SCNN1A	1,300
ARHGAP10	493

Intra-cohort edges

A	B	Sources
NR3C2	SCNN1A	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR3C2	P08235	30
SCNN1A	P37088	3
ARHGAP21	Q5T5U3	3
ARHGAP10	A1A4S6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of PAK-2p34 activity by PS-GAP/RHG10	1	1427.5×	0.011	ARHGAP10
RHOA GTPase cycle	2	37.3×	0.011	ARHGAP21, ARHGAP10
CDC42 GTPase cycle	2	36.1×	0.011	ARHGAP21, ARHGAP10
RAC1 GTPase cycle	2	30.5×	0.011	ARHGAP21, ARHGAP10
Sensory perception of salty taste	1	475.8×	0.012	SCNN1A
SUMOylation of intracellular receptors	1	84.0×	0.041	NR3C2
Sensory perception of taste	1	84.0×	0.041	SCNN1A
RHOF GTPase cycle	1	64.9×	0.041	ARHGAP21
RND3 GTPase cycle	1	64.9×	0.041	ARHGAP21
RHOD GTPase cycle	1	51.0×	0.041	ARHGAP21
Nuclear Receptor transcription pathway	1	50.1×	0.041	NR3C2
RHOJ GTPase cycle	1	50.1×	0.041	ARHGAP21
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	48.4×	0.041	NR3C2
RHOQ GTPase cycle	1	45.3×	0.041	ARHGAP21
SUMO E3 ligases SUMOylate target proteins	1	44.6×	0.041	NR3C2
SUMOylation	1	40.8×	0.041	NR3C2
RHOB GTPase cycle	1	38.6×	0.041	ARHGAP21
RHOG GTPase cycle	1	37.1×	0.041	ARHGAP21
RHOC GTPase cycle	1	36.6×	0.041	ARHGAP21
Stimuli-sensing channels	1	34.0×	0.042	SCNN1A
RAC2 GTPase cycle	1	31.7×	0.043	ARHGAP21
RAC3 GTPase cycle	1	29.7×	0.044	ARHGAP21
Ion channel transport	1	24.0×	0.050	SCNN1A
Sensory Perception	1	23.8×	0.050	SCNN1A
Cellular responses to stress	1	9.2×	0.121	NR3C2
Cellular responses to stimuli	1	7.9×	0.135	NR3C2
Transport of small molecules	1	6.3×	0.161	SCNN1A
Post-translational protein modification	1	4.8×	0.200	NR3C2
Metabolism of proteins	1	3.1×	0.286	NR3C2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory perception of salty taste	1	1053.2×	0.005	SCNN1A
maintenance of Golgi location	1	1053.2×	0.005	ARHGAP21
cellular response to aldosterone	1	601.9×	0.005	SCNN1A
nuclear receptor-mediated steroid hormone signaling pathway	1	526.6×	0.005	NR3C2
Golgi localization	1	526.6×	0.005	ARHGAP21
cellular response to vasopressin	1	526.6×	0.005	SCNN1A
establishment of Golgi localization	1	468.1×	0.005	ARHGAP21
multicellular organismal-level water homeostasis	1	421.3×	0.005	SCNN1A
sensory perception of sour taste	1	421.3×	0.005	SCNN1A
regulation of small GTPase mediated signal transduction	2	72.0×	0.005	ARHGAP21, ARHGAP10
signal transduction	3	12.0×	0.005	ARHGAP21, ARHGAP10, NR3C2
organelle transport along microtubule	1	300.9×	0.006	ARHGAP21
sodium ion homeostasis	1	234.1×	0.008	SCNN1A
intracellular sodium ion homeostasis	1	191.5×	0.008	SCNN1A
cellular response to acidic pH	1	183.2×	0.008	SCNN1A
sodium ion import across plasma membrane	1	156.0×	0.009	SCNN1A
positive regulation of non-canonical NF-kappaB signal transduction	1	63.8×	0.021	NR3C2
regulation of blood pressure	1	55.4×	0.023	SCNN1A
sodium ion transmembrane transport	1	50.8×	0.024	SCNN1A
Golgi organization	1	33.4×	0.033	ARHGAP21
cytoskeleton organization	1	33.2×	0.033	ARHGAP10
negative regulation of apoptotic process	1	8.7×	0.115	ARHGAP10
regulation of transcription by RNA polymerase II	1	2.9×	0.302	NR3C2

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Enalapril, Sodium Polystyrene Sulfonate.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SCNN1A	AMILORIDE
NR3C2	PROGESTERONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR3C2	24	4
SCNN1A	2	4
ARHGAP21	0	0
ARHGAP10	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMILORIDE	4	SCNN1A
PROGESTERONE	4	NR3C2
EPLERENONE	4	NR3C2
MIFEPRISTONE	4	NR3C2
PREDNISOLONE	4	NR3C2
BUDESONIDE	4	NR3C2
SPIRONOLACTONE	4	NR3C2
FLUTICASONE PROPIONATE	4	NR3C2
FLUTICASONE FUROATE	4	NR3C2
HYDROCORTISONE BUTYRATE	4	NR3C2
FINERENONE	4	NR3C2
DEXAMETHASONE	4	NR3C2
HYDROCORTISONE	4	NR3C2
MEDROXYPROGESTERONE ACETATE	4	NR3C2
CORTICOSTERONE	3	NR3C2
ASOPRISNIL	3	NR3C2
BALCINRENONE	3	NR3C2
552-02 FREE BASE	2	SCNN1A
METRIBOLONE	2	NR3C2
ONAPRISTONE	2	NR3C2
MT-3995	2	NR3C2
ALDOSTERONE	2	NR3C2
STANOLONE	2	NR3C2
LY2623091	2	NR3C2
TUROFEXORATE ISOPROPYL	2	NR3C2
PF-03882845	1	NR3C2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NR3C2	286	Binding:195, Functional:89, ADMET:2
SCNN1A	6	Binding:4, ADMET:1, Functional:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NR3C2	286

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

26 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
AMILORIDE	4	SCNN1A
PROGESTERONE	4	NR3C2
EPLERENONE	4	NR3C2
MIFEPRISTONE	4	NR3C2
PREDNISOLONE	4	NR3C2
BUDESONIDE	4	NR3C2
SPIRONOLACTONE	4	NR3C2
FLUTICASONE PROPIONATE	4	NR3C2
FLUTICASONE FUROATE	4	NR3C2
HYDROCORTISONE BUTYRATE	4	NR3C2
FINERENONE	4	NR3C2
DEXAMETHASONE	4	NR3C2
HYDROCORTISONE	4	NR3C2
MEDROXYPROGESTERONE ACETATE	4	NR3C2
CORTICOSTERONE	3	NR3C2
ASOPRISNIL	3	NR3C2
BALCINRENONE	3	NR3C2
552-02 FREE BASE	2	SCNN1A
METRIBOLONE	2	NR3C2
ONAPRISTONE	2	NR3C2
MT-3995	2	NR3C2
ALDOSTERONE	2	NR3C2
STANOLONE	2	NR3C2
LY2623091	2	NR3C2
TUROFEXORATE ISOPROPYL	2	NR3C2
PF-03882845	1	NR3C2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SCNN1A, NR3C2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ARHGAP21, ARHGAP10

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ARHGAP21	0	—
ARHGAP10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00004328	PHASE2	COMPLETED	Phase II Study of the Pathophysiology and Treatment With Enalapril and Polystyrene Sulfonate for Pseudohypoaldosteronism, Type I
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT06905600	Not specified	RECRUITING	Transient Pseudohypoaldosteronism Affecting Children With Urinary Tract Malformation
NCT00323167	Not specified	COMPLETED	Rare Genetic Disorders of the Breathing Airways
NCT00368446	Not specified	COMPLETED	Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ENALAPRIL	4	3
SODIUM POLYSTYRENE SULFONATE	4	1