Pseudohypoaldosteronism type 2E is the CUL3-related form of familial hyperkalaemic hypertension (FHHt, also called pseudohypoaldosteronism type 2 or Gordon syndrome), and the most severe of its four genetic subtypes. Heterozygous and frequently de novo CUL3 variants clustered around the exon 9 splice sites all converge on skipping of exon 9, producing an in-frame deletion of residues 403 to 459 from cullin-3 (CUL3-delta9). Cullin-3 is the scaffold of a cullin-RING E3 ubiquitin ligase that, bound to the substrate adaptor KLHL3, ubiquitinates WNK1 and WNK4 for proteasomal degradation in the distal convoluted tubule. CUL3-delta9 cannot ubiquitinate WNK kinases efficiently and also depletes KLHL3, so WNK kinases accumulate, activate the downstream kinases SPAK and OSR1, and these phosphorylate and activate the thiazide-sensitive Na-Cl cotransporter NCC. The resulting salt retention raises blood pressure while reducing potassium and hydrogen ion secretion, giving hypertension with hyperkalaemia, hyperchloraemic metabolic acidosis and suppressed renin despite a normal glomerular filtration rate. Cullin-3 also turns over RhoA and phosphodiesterase 5 in vascular smooth muscle, and a knock-in mouse model shows arterial pulse waveform changes, so a vascular contribution to the hypertension is recognised alongside the renal one. Children typically present earlier and more severely than in the WNK and KLHL3 subtypes, sometimes with short stature, and low-dose thiazide diuretics correct both the electrolyte disturbance and the blood pressure.
Ask a research question about Pseudohypoaldosteronism Type 2E. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
Conditions with similar clinical presentations that must be differentiated from Pseudohypoaldosteronism Type 2E:
name: Pseudohypoaldosteronism Type 2E
category: Mendelian
creation_date: "2026-10-30T00:00:00Z"
synonyms:
- PHA2E
- CUL3 pseudohypoaldosteronism type 2
- pseudohypoaldosteronism type 2 caused by mutation in CUL3
- pseudohypoaldosteronism type IIE
- familial hypertension with hyperkalaemia - CUL3
description: >-
Pseudohypoaldosteronism type 2E is the CUL3-related form of familial
hyperkalaemic hypertension (FHHt, also called pseudohypoaldosteronism type 2
or Gordon syndrome), and the most severe of its four genetic subtypes.
Heterozygous and frequently de novo CUL3 variants clustered around the exon 9
splice sites all converge on skipping of exon 9, producing an in-frame
deletion of residues 403 to 459 from cullin-3 (CUL3-delta9). Cullin-3 is the
scaffold of a cullin-RING E3 ubiquitin ligase that, bound to the substrate
adaptor KLHL3, ubiquitinates WNK1 and WNK4 for proteasomal degradation in the
distal convoluted tubule. CUL3-delta9 cannot ubiquitinate WNK kinases
efficiently and also depletes KLHL3, so WNK kinases accumulate, activate the
downstream kinases SPAK and OSR1, and these phosphorylate and activate the
thiazide-sensitive Na-Cl cotransporter NCC. The resulting salt retention
raises blood pressure while reducing potassium and hydrogen ion secretion,
giving hypertension with hyperkalaemia, hyperchloraemic metabolic acidosis and
suppressed renin despite a normal glomerular filtration rate. Cullin-3 also
turns over RhoA and phosphodiesterase 5 in vascular smooth muscle, and a
knock-in mouse model shows arterial pulse waveform changes, so a vascular
contribution to the hypertension is recognised alongside the renal one.
Children typically present earlier and more severely than in the WNK and
KLHL3 subtypes, sometimes with short stature, and low-dose thiazide diuretics
correct both the electrolyte disturbance and the blood pressure.
disease_term:
preferred_term: pseudohypoaldosteronism type 2E
term:
id: MONDO:0013782
label: pseudohypoaldosteronism type 2E
parents:
- Pseudohypoaldosteronism type 2
- Autosomal dominant disease
notes: >-
No GeneReviews chapter covers pseudohypoaldosteronism type 2E, familial
hyperkalaemic hypertension or Gordon syndrome, and no StatPearls chapter names
the disease either (`just check-genereviews --online` against the committed
Bookshelf index snapshot of 2026-09-10 reported NO_CHAPTER on both lines with
the entry's five synonyms in place). The phenotype baseline here is therefore
the Boyden 2012 discovery cohort, the Orphanet record, individual case
reports and the mechanism literature.
Name collision. "Gordon syndrome" is an eponym for two unrelated diseases:
this renal tubular disorder, and the PIEZO2 distal arthrogryposis type 3
curated as `Gordon_Syndrome` (MONDO:0007252). A literature search on the
eponym returns both. Papers cited here were each checked for which entity
they describe; PMID:34480842 uses the eponym in its title for the renal
disease and reports a CUL3 intron 9 variant, hyperkalaemia and hypertension,
so it is this disease.
Allele spectrum. Every reported PHA2E allele acts through exon 9 skipping,
but the variants that cause it are heterogeneous in type: canonical splice
donor and acceptor variants, deeper intronic variants, and at least one
synonymous exonic variant (c.1221A>G p.Glu407Glu) that removes exonic
splicing enhancer sequence. A CUL3 variant list is therefore not interpretable
for this disease without a splicing readout.
Mechanism direction is contested, and the entry records that rather than
choosing. Whether CUL3-delta9 is hyperneddylated or under-neddylated is
directly disputed between PMID:25250572 and PMID:26100637; see the
`cul3_delta9_neddylation_direction` discussion. ClinGen's own evidence summary
for this gene-disease pair calls the mechanism loss of function, while the
cell-based work describes dominant-negative action on the wild-type allele,
which is why `functional_impact_category` is `DOMINANT_NEGATIVE` here and the
ClinGen wording is noted on the validity assertion rather than overwritten.
Aldosterone direction is disputed too, and the disease name misleads about it.
Despite "pseudohypoaldosteronism", the usual report in type 2 is a normal or
high aldosterone with a low renin: the kidney behaves as though aldosterone
were absent while it is not. PMID:27369102 states aldosterone is most
frequently normal or high, while PMID:41380172 reports a CUL3 patient whose
aldosterone was suppressed along with renin, which is what led to
fludrocortisone being given for a presumed aldosterone deficiency. The
`Decreased circulating aldosterone concentration` phenotype carries both, one
as SUPPORT and one as REFUTE, and no frequency.
Hypercalciuria is recorded as a phenotype but deliberately left out of the
causal graph. Activated NCC raising distal calcium excretion, the mirror of
thiazide-induced hypocalciuria, is the obvious reading, but none of the
sources cited here states it, so no edge is drawn.
classifications:
harrisons_chapter:
- classification_value: KIDNEY_URINARY_TRACT
- classification_value: GENETICS_ENVIRONMENT_DISEASE
references:
- reference: PMID:22266938
title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
- reference: PMID:26286618
title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
- reference: PMID:32852625
title: "Cullin-3: Renal and Vascular Mechanisms Regulating Blood Pressure."
- reference: PMID:27369102
title: "[Gordon syndrome: The importance of measuring blood pressure in children]."
- reference: PMID:31813255
title: "Hypertension-causing cullin 3 mutations disrupt COP9 signalosome binding."
- reference: ORPHA:300530
title: "Pseudohypoaldosteronism type 2E"
inheritance:
- name: Autosomal dominant inheritance, frequently de novo
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Every reported PHA2E allele is heterozygous and transmits as an autosomal
dominant trait. A high proportion arise de novo, which distinguishes the
CUL3 subtype from the KLHL3 subtype, where both dominant and recessive
alleles occur.
evidence:
- reference: PMID:22266938
reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo."
explanation: >-
States both the dominant transmission and the predominance of de novo
origin for the CUL3 subtype, against the KLHL3 comparison.
- reference: ORPHA:300530
reference_title: "Pseudohypoaldosteronism type 2E"
supports: SUPPORT
evidence_source: OTHER
snippet: "Autosomal dominant"
explanation: Orphanet records autosomal dominant inheritance for this subtype.
prevalence:
- population: Worldwide
measure_type: POINT_PREVALENCE
prevalence_class: BELOW_1_IN_1000000
notes: >-
Orphanet assigns this subtype a worldwide point prevalence class of below 1
in 1,000,000 and records the remainder of its epidemiology as cases and
families rather than a rate.
evidence:
- reference: ORPHA:300530
reference_title: "Pseudohypoaldosteronism type 2E"
supports: SUPPORT
evidence_source: OTHER
snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
explanation: Orphanet epidemiology row giving the worldwide point-prevalence class.
genetic:
- name: CUL3
association: Causative, heterozygous and predominantly de novo
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: CUL3
term:
id: hgnc:2553
label: CUL3
gene_disease_validity:
- validity_classification: DEFINITIVE
classified_by: CLINGEN
external_id: CGGV:assertion_f697fb5e-72de-4116-9cad-706e2d651268-2021-12-01T013000.000Z
notes: >-
The same ClinGen record calls the mechanism of pathogenicity loss of
function. The cell-based literature describes dominant-negative action on
the wild-type allele instead, so the two are recorded separately rather
than reconciled here.
evidence:
- reference: CGGV:assertion_f697fb5e-72de-4116-9cad-706e2d651268-2021-12-01T013000.000Z
reference_title: "CUL3 / pseudohypoaldosteronism type 2E (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "CUL3 | HGNC:2553 | pseudohypoaldosteronism type 2E | MONDO:0013782 | AD | Definitive"
explanation: >-
The ClinGen Tubulopathy Gene Curation Expert Panel row classifying the
CUL3 to PHA2E relationship as Definitive under autosomal dominant
inheritance.
notes: >-
The disease alleles are heterogeneous as sequence changes and homogeneous in
consequence. ClinGen's curation includes nine variants described as
intronic, canonical splice, splice donor, splice acceptor and splice
enhancer across eight probands in four publications.
evidence:
- reference: PMID:22266938
reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families."
explanation: >-
The exome study that identified CUL3 as a cause of PHAII, establishing the
gene-disease relationship.
- reference: PMID:29511623
reference_title: "A novel mutation in exon 9 of Cullin 3 gene contributes to aberrant splicing in pseudohypoaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "For CUL3, all mutations associated with PHAII exclusively lead to exon 9 skipping."
explanation: >-
States that the whole reported CUL3 allele spectrum converges on one
splicing consequence, which is what makes a splicing readout necessary to
interpret a variant.
- reference: PMID:24266877
reference_title: "Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have demonstrated conclusively, in two unrelated affected individuals, that rare intronic variants in CUL3 cause the skipping of exon 9 as has been proposed previously."
explanation: >-
Direct demonstration in patients that intronic CUL3 variants produce exon
9 skipping, rather than the skipping being inferred from the variant
position.
- reference: PMID:27369102
reference_title: "[Gordon syndrome: The importance of measuring blood pressure in children]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The genetic analysis proved the existence of a splice mutation on exon 9 of the CUL3 gene coding for cullin 3. This mutation is de novo."
explanation: >-
A further de novo CUL3 exon 9 splice variant in a child, supporting both
the allele class and the predominance of de novo origin.
variants:
- name: c.1377+1G>C
variant_type: single nucleotide variant
clinical_significance: PATHOGENIC
description: >-
De novo intron 9 splice donor variant reported in a 7-year-old boy whose
hypertension, hyperkalaemia and metabolic acidosis were found during
evaluation of short stature.
evidence:
- reference: PMID:34480842
reference_title: "Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Genetic analysis revealed a heterozygous de novo mutation in the CUL3 gene (c.1377+1G > C in intron 9)."
explanation: Reports the variant, its zygosity and its de novo origin.
- name: c.1207-2A>C
variant_type: single nucleotide variant
clinical_significance: PATHOGENIC
description: >-
De novo splice acceptor variant reported in a child who presented at 2
years 7 months with recurrent vomiting and was initially misdiagnosed as
an aldosterone deficiency state.
evidence:
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report a pediatric patient with early-onset PHA2 caused by a de novo splice-site variant (c.1207-2A>C) in the CUL3 gene."
explanation: Reports the variant and its de novo origin in early-onset disease.
- name: c.1221A>G (p.Glu407Glu)
variant_type: single nucleotide variant
clinical_significance: PATHOGENIC
description: >-
Synonymous exonic variant in a Chinese kindred that nonetheless causes
complete exon 9 skipping, apparently by reducing the ratio of exonic
splicing enhancer to silencer sequence. A synonymous change is the case
that makes protein-level variant interpretation fail for this gene.
evidence:
- reference: PMID:29511623
reference_title: "A novel mutation in exon 9 of Cullin 3 gene contributes to aberrant splicing in pseudohypoaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We obtained evidence that this synonymous mutation leads to complete exon 9 skipping, and in silico bioinformatics analysis demonstrated that the CUL3 c.1221A > G mutation might decrease the ratio of exonic splicing enhancers and silencers."
explanation: >-
Establishes that a synonymous coding change produces the same exon 9
skipping as the splice-site alleles.
pathophysiology:
- name: CUL3 Exon 9 Skipping
biological_scale: MOLECULAR
description: >-
Heterozygous CUL3 variants of several different types, intronic, canonical
splice donor, splice acceptor and synonymous exonic, all cause skipping of
exon 9 during splicing of the CUL3 transcript. The transcript stays in
frame, so a stable protein lacking residues 403 to 459 is produced rather
than a null allele.
genes:
- preferred_term: CUL3
term:
id: hgnc:2553
label: CUL3
molecular_functions:
- preferred_term: cullin-3 ubiquitin ligase complex scaffold activity
term:
id: GO:0160072
label: ubiquitin ligase complex scaffold activity
description: >-
What the affected protein does: cullin-3 assembles the CRL3 complex,
binding BTB-domain substrate adaptors at its N terminus and RBX1 at its C
terminus, and does not itself catalyse ubiquitin transfer. No modifier is
set because the direction is exactly what the literature disputes:
adaptor binding is retained, and reported as increased, while the ligase
output of the complex falls.
genetic_context:
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
functional_impact_category: DOMINANT_NEGATIVE
description: >-
Heterozygous germline alleles. The deleted protein acts on the
wild-type allele's activity as well as losing its own, which is why the
impact is recorded as dominant negative rather than as a simple loss of
function.
downstream:
- target: Loss of CUL3-delta9 Interaction with Cullin Regulators
causal_link_type: DIRECT
description: >-
The 57-residue deletion sits at the border of the cullin N-terminal and
C-terminal domains and alters folding there, which is what removes the
regulator binding sites.
evidence:
- reference: PMID:29897280
reference_title: "Dual gain and loss of cullin 3 function mediates familial hyperkalemic hypertension."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We first identified that the catalytically active CSN subunit jun activation domain-binding protein-1 (JAB1) does not associate with the deleted Cul3 4-helix bundle domain but instead with the adjacent α/β1 domain, suggesting that altered protein folding underlies the impaired binding."
explanation: >-
Connects the deletion to loss of COP9 signalosome binding through
altered folding, which is the step this edge asserts.
evidence:
- reference: PMID:22266938
reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion."
explanation: >-
Establishes both the shared splicing consequence and that the product is
an in-frame deletion rather than a truncation.
- reference: PMID:29869755
reference_title: "Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "PHAII-causing CUL3 mutations mediate exon9 skipping, producing a CUL3 protein with a 57-amino acid deletion (Δ403-459)."
explanation: >-
Gives the residue span of the deletion. The quote is the background
statement of the human genetics in a mouse paper, so the evidence it
describes is human clinical rather than the paper's own mouse work.
- name: Loss of CUL3-delta9 Interaction with Cullin Regulators
biological_scale: MOLECULAR
description: >-
CUL3-delta9 loses its interaction with the COP9 signalosome, which
deneddylates cullins, and with CAND1, which exchanges substrate adaptors.
Cullin-RING ligase activity depends on cycling between neddylated and
deneddylated states rather than on neddylation alone, so losing both
regulators dysregulates the cycle. The direction of the resulting
neddylation change is disputed in the literature and is recorded as an open
question rather than asserted here.
biological_processes:
- preferred_term: protein neddylation
term:
id: GO:0045116
label: protein neddylation
cellular_components:
- preferred_term: Cul3-RING ubiquitin ligase complex
term:
id: GO:0031463
label: Cul3-RING ubiquitin ligase complex
downstream:
- target: CUL3-delta9 Ubiquitin Ligase Dysfunction
causal_link_type: DIRECT
evidence:
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Instead, CUL3(Δ403-459) auto-ubiquitylates and loses interaction with two important Cullin regulators: the COP9-signalosome and CAND1."
explanation: >-
Reports the loss of both regulator interactions, and the
auto-ubiquitination that accompanies it.
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "While neddylation is required for efficient ubiquitylation, studies show that the cycling between a neddylated and deneddylated state is crucial in a cellular context"
explanation: >-
Supports the claim that it is the neddylation cycle rather than
neddylation level alone that activity depends on, which is why losing the
deneddylase complex matters.
- name: CUL3-delta9 Ubiquitin Ligase Dysfunction
biological_scale: MOLECULAR
description: >-
CUL3-delta9 retains RBX1 binding and KLHL3 binding but cannot ubiquitinate
WNK kinases efficiently, and it cannot degrade WNK4 on its own. It also
binds substrate adaptors more avidly than wild-type cullin-3 and forms
unstable dimers with the wild-type protein, reducing the amount of active
wild-type complex, so the single mutant allele impairs the normal allele as
well.
biological_processes:
- preferred_term: protein ubiquitination
term:
id: GO:0016567
label: protein ubiquitination
modifier: DECREASED
downstream:
- target: KLHL3 Depletion
causal_link_type: DIRECT
evidence:
- reference: PMID:29897280
reference_title: "Dual gain and loss of cullin 3 function mediates familial hyperkalemic hypertension."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In conclusion, deletion of exon 9 from Cul3 generates a protein that is itself ubiquitin-ligase defective but also capable of enhanced autophagocytic KLHL3 degradation, thereby exerting dominant-negative effects on the WT allele."
explanation: >-
States both halves of this edge: the ligase defect, and the enhanced
degradation of KLHL3 that follows from it.
- target: RhoA Accumulation in Vascular Smooth Muscle
causal_link_type: DIRECT
evidence:
- reference: PMID:26100637
reference_title: "Hypertension-causing Mutations in Cullin3 Protein Impair RhoA Protein Ubiquitination and Augment the Association with Substrate Adaptors."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We conclude that Cul3Δ9-associated ubiquitin ligase activity toward RhoA is impaired and suggest that Cul3Δ9 mutations may act dominantly by sequestering substrate adaptors and disrupting Cul3WT complexes."
explanation: >-
Reports impaired ligase activity toward RhoA specifically, which is the
step from the general ligase defect to RhoA accumulation.
evidence:
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We report here that the PHA2E mutant, CUL3(Δ403-459), is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility."
explanation: >-
Reports the loss of WNK ubiquitination activity by the disease protein,
which is the defect this node names.
- reference: PMID:29897280
reference_title: "Dual gain and loss of cullin 3 function mediates familial hyperkalemic hypertension."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In the absence of WT Cul3, WNK4 was not degraded, demonstrating that Cul3Δ403-459 itself cannot degrade WNK4; conversely, when WT Cul3 was present, as in diseased humans, WNK4 degradation was restored."
explanation: >-
Shows directly that the mutant protein alone cannot degrade WNK4, and
that the heterozygous state is what the disease actually depends on.
- reference: PMID:26100637
reference_title: "Hypertension-causing Mutations in Cullin3 Protein Impair RhoA Protein Ubiquitination and Augment the Association with Substrate Adaptors."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Cul3Δ9 also forms unstable dimers with Cul3WT, disrupting dimers of Cul3WT complexes that are required for efficient ubiquitination of some substrates."
explanation: >-
Supports the dominant-negative component of this node, that the mutant
protein reduces active wild-type complex rather than only failing itself.
- name: KLHL3 Depletion
biological_scale: MOLECULAR
description: >-
KLHL3, the substrate adaptor that presents WNK kinases to cullin-3, falls in
abundance in the presence of CUL3-delta9. Degradation runs through both the
proteasome and autophagy. In knock-in mice the fall is specific to KLHL3:
other KLHL family proteins such as KLHL2 are unchanged. Because the adaptor
is what recruits the substrate, losing it blocks WNK degradation even by the
remaining wild-type cullin-3.
biological_processes:
- preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process
term:
id: GO:0043161
label: proteasome-mediated ubiquitin-dependent protein catabolic process
modifier: INCREASED
downstream:
- target: WNK Kinase Accumulation
causal_link_type: DIRECT
evidence:
- reference: PMID:25250572
reference_title: "Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These results indicate that FHHt-associated CUL3 Δ403-459 targets KLHL3 for degradation, thereby preventing WNK degradation"
explanation: >-
States the causal step from KLHL3 degradation to failure of WNK
degradation, which is exactly this edge.
evidence:
- reference: PMID:29869755
reference_title: "Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These findings indicate that the decreased abundance of KLHL3 is a specific phenomenon caused by mutant CUL3 (Δexon9)."
explanation: >-
Confirms the KLHL3 fall in vivo in knock-in mice and that it is specific
to KLHL3 rather than a general effect on KLHL proteins.
- reference: PMID:29897280
reference_title: "Dual gain and loss of cullin 3 function mediates familial hyperkalemic hypertension."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Proteasomal KLHL3 degradation was enhanced by Cul3Δ403-459; however, autophagic degradation was also upregulated by this Cul3 mutant."
explanation: >-
Supports that KLHL3 is removed by two routes, proteasomal and autophagic,
rather than by the proteasome alone.
- name: WNK Kinase Accumulation
biological_scale: MOLECULAR
description: >-
WNK1 and WNK4, normally held at low abundance by CUL3-KLHL3 mediated
ubiquitination and proteasomal degradation, accumulate in the distal
nephron. The accumulation is of protein level rather than of intrinsic
kinase activity, and it is the common endpoint shared with the WNK1, WNK4
and KLHL3 subtypes of the disease.
cell_types:
- preferred_term: kidney distal convoluted tubule epithelial cell
term:
id: CL:1000849
label: kidney distal convoluted tubule epithelial cell
downstream:
- target: SPAK and OSR1 Activation
causal_link_type: DIRECT
evidence:
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: "When activated by phosphorylation, the WNK kinases phosphorylate and activate the downstream kinases, SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1)"
explanation: >-
States the WNK to SPAK/OSR1 step. The sentence is the paper's
background summary of established pathway work it cites rather than its
own result.
evidence:
- reference: PMID:27378813
reference_title: "ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The loss of functionality of CUL3(Δ403-459) and secondary accumulation of WNK kinases causes substantial NCC activation."
explanation: >-
Names the secondary accumulation of WNK kinases as the consequence of the
CUL3 defect in the knock-in model.
- reference: PMID:25250572
reference_title: "Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "As predicted, nephron-specific deletion of Cul3 in mice did increase WNK kinase levels and the abundance of phosphorylated Na-Cl cotransporter (NCC)."
explanation: >-
Shows in vivo that removing cullin-3 activity from the nephron raises WNK
kinase levels and phosphorylated NCC together.
- name: SPAK and OSR1 Activation
biological_scale: MOLECULAR
description: >-
Accumulated WNK kinases phosphorylate and activate the downstream
serine/threonine kinases SPAK and OSR1, which are the direct kinases for the
cation-chloride cotransporters.
biological_processes:
- preferred_term: protein phosphorylation
term:
id: GO:0006468
label: protein phosphorylation
modifier: INCREASED
downstream:
- target: NCC Phosphorylation and Overactivity
causal_link_type: DIRECT
evidence:
- reference: PMID:27378813
reference_title: "ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation."
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: "which in turn phosphorylate and activate SLC-type cation-chloride cotransporters in the kidney, such as NCC, leading to an increased sodium ion reabsorption"
explanation: >-
States the SPAK/OSR1 to NCC step and its transport consequence. The
sentence is the paper's background account of the established cascade.
evidence:
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: "which in turn phosphorylate and activate cation–chloride co-transporters in the kidney, such as NCC (Na+/Cl− co-transporter), which leads to increased sodium ion reabsorption"
explanation: >-
Supports that activated SPAK and OSR1 act on NCC. Quoted from the paper's
background summary of the pathway rather than from its own experiments.
- name: NCC Phosphorylation and Overactivity
biological_scale: CELLULAR
description: >-
The thiazide-sensitive Na-Cl cotransporter NCC (SLC12A3) on the apical
membrane of distal convoluted tubule cells is phosphorylated and activated.
This is the step thiazide diuretics inhibit, which is why the disease is
thiazide-reversible.
cell_types:
- preferred_term: kidney distal convoluted tubule epithelial cell
term:
id: CL:1000849
label: kidney distal convoluted tubule epithelial cell
molecular_functions:
- preferred_term: sodium:chloride symporter activity
term:
id: GO:0015378
label: sodium:chloride symporter activity
modifier: INCREASED
downstream:
- target: Increased Distal Nephron Salt Reabsorption
causal_link_type: DIRECT
evidence:
- reference: PMID:25250572
reference_title: "Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "As predicted, nephron-specific deletion of Cul3 in mice did increase WNK kinase levels and the abundance of phosphorylated Na-Cl cotransporter (NCC)."
explanation: >-
Reports increased phosphorylated NCC, the activated form, when nephron
cullin-3 activity is lost.
- reference: PMID:27378813
reference_title: "ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The loss of functionality of CUL3(Δ403-459) and secondary accumulation of WNK kinases causes substantial NCC activation."
explanation: Reports substantial NCC activation in the CUL3-delta9 knock-in model.
- name: Increased Distal Nephron Salt Reabsorption
biological_scale: TISSUE
description: >-
Overactive NCC reabsorbs sodium and chloride in the distal convoluted
tubule. Because sodium delivered more distally is the driving force for
potassium and hydrogen ion secretion in the collecting duct, taking it up
earlier both expands volume and reduces the gradient available for
potassium and acid excretion. This single step therefore produces the
hypertension and the electrolyte picture together, and it is salt-dependent:
dietary salt restriction alone improves it.
biological_processes:
- preferred_term: sodium ion transmembrane transport
term:
id: GO:0035725
label: sodium ion transmembrane transport
modifier: INCREASED
downstream:
- target: Hypertension
causal_link_type: DIRECT
evidence:
- reference: PMID:24266877
reference_title: "Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome)."
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: "FHHt (familial hyperkalaemic hypertension; also known as Gordon's syndrome) is a salt-dependent form of hypertension caused by mutations in the regulators of the thiazide-sensitive Na+-Cl- co-transporter NCC"
explanation: >-
States that the hypertension is salt-dependent and arises from
dysregulation of NCC, which is the edge from salt reabsorption to blood
pressure.
- target: Hyperkalemia
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Partly, not wholly, explained by NCC activation. Two independent sources
state that the hyperkalaemia is only partly driven by NCC, and the
candidate additional mechanism of reduced ROMK expression was tested and
not found in the knock-in mouse.
evidence:
- reference: PMID:27378813
reference_title: "ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation."
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: "Subjects with FHHt also have abnormalities in other electrolyte flux pathways showing typically hyperkalemia and metabolic acidosis, that is only partly driven by NCC activation"
explanation: >-
Supports the link while recording that it is partial, which is why the
edge is typed as having known intermediates rather than direct.
- target: Hyperchloremic metabolic acidosis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: "These patients also present with disturbed plasma electrolytes especially hyperkalaemia and a metabolic acidosis, partly driven by NCC activation"
explanation: >-
Links NCC activation to the acidosis, and states that the link is
partial.
- target: Decreased circulating renin concentration
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Volume expansion from salt retention suppresses renin release, which is
why renin is low despite the hyperkalaemia that would otherwise raise
aldosterone.
evidence:
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Pseudohypoaldosteronism type 2 (PHA2) is a rare autosomal dominant electrolyte disorder characterized by hypertension, hyperkalemia, metabolic acidosis, and suppressed renin activity, usually with preserved renal function."
explanation: >-
Names suppressed renin alongside the salt-retention phenotype as part of
the defining picture.
evidence:
- reference: PMID:24266877
reference_title: "Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The results of the present study support the existing evidence that the CUL3 and KLHL3 gene products are physiologically important regulators of thiazide-sensitive distal nephron NaCl reabsorption"
explanation: >-
Places CUL3 as a regulator of distal nephron NaCl reabsorption, the
process this node names.
- name: RhoA Accumulation in Vascular Smooth Muscle
biological_scale: MOLECULAR
description: >-
Cullin-3 also turns over RhoA and phosphodiesterase 5 in vascular smooth
muscle. CUL3-delta9 ubiquitinates RhoA poorly, so RhoA accumulates. This is
an extra-renal arm of the same molecular defect rather than a consequence of
the renal salt handling.
cell_types:
- preferred_term: vascular associated smooth muscle cell
term:
id: CL:0000359
label: vascular associated smooth muscle cell
biological_processes:
- preferred_term: Rho protein signal transduction
term:
id: GO:0007266
label: Rho protein signal transduction
modifier: INCREASED
downstream:
- target: Impaired Vasodilation and Enhanced Vasoconstriction
causal_link_type: DIRECT
evidence:
- reference: PMID:32852625
reference_title: "Cullin-3: Renal and Vascular Mechanisms Regulating Blood Pressure."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The consequent accumulation of substrates and overactivation of downstream signaling cause FHHt through increased sodium reabsorption, enhanced vasoconstriction, and decreased vasodilation."
explanation: >-
States that substrate accumulation produces enhanced vasoconstriction
and decreased vasodilation, which is this edge. Quoted from a review
synthesising work it did not perform.
evidence:
- reference: PMID:26100637
reference_title: "Hypertension-causing Mutations in Cullin3 Protein Impair RhoA Protein Ubiquitination and Augment the Association with Substrate Adaptors."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "When expressed in these cells, Cul3Δ9 supported reduced ubiquitin ligase activity toward RhoA compared with equivalent levels of wild-type Cul3 (Cul3WT)."
explanation: >-
Reports reduced ligase activity toward RhoA for the disease protein, which
is what causes RhoA to accumulate.
- reference: PMID:32852625
reference_title: "Cullin-3: Renal and Vascular Mechanisms Regulating Blood Pressure."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Cul3-based ubiquitin ligase regulates renal electrolyte transport, vascular tone, and redox homeostasis by facilitating the normal turnover of (1) with-no-lysine kinases in the distal nephron, (2) RhoA and phosphodiesterase 5 in the vascular smooth muscle, and (3) nuclear factor E2-related factor 2 in antioxidant responses."
explanation: >-
Names RhoA in vascular smooth muscle as a cullin-3 substrate, establishing
that this cell type and substrate are part of cullin-3 blood pressure
control.
- name: Impaired Vasodilation and Enhanced Vasoconstriction
biological_scale: TISSUE
description: >-
Increased RhoA signalling and reduced phosphodiesterase 5 turnover in
vascular smooth muscle raise vascular tone and blunt nitric-oxide-mediated
vasodilation. The CUL3-delta9 knock-in mouse shows arterial pulse waveform
changes, a vascular sign not reported in the WNK and KLHL3 mouse models,
which is the direct evidence that the vascular arm contributes to the
hypertension here.
biological_processes:
- preferred_term: vasodilation
term:
id: GO:0042311
label: vasodilation
modifier: DECREASED
downstream:
- target: Hypertension
causal_link_type: DIRECT
evidence:
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models."
explanation: >-
The authors' own inference that a vascular change contributes to the
hypertension in this model, which is the edge asserted here.
evidence:
- reference: PMID:32852625
reference_title: "Cullin-3: Renal and Vascular Mechanisms Regulating Blood Pressure."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "It is no longer controversial that CUL3 mutations cause familial hyperkalemic hypertension (FHHt, a rare genetic disease also known as Pseudohypoaldosteronism or Gordon Syndrome) through both renal and vascular mechanisms"
explanation: >-
Supports treating the vascular arm as established rather than speculative,
alongside the renal arm.
phenotypes:
- category: Clinical
name: Hypertension
frequency: VERY_FREQUENT
description: >-
Hypertension is a defining feature and is the usual reason for referral in
older children and adults. It responds to low-dose thiazide, although one
reported child treated from age 7 had persistent hypertension on follow-up.
phenotype_term:
preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
evidence:
- reference: PMID:22266938
reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis"
explanation: >-
Names hypertension as one of the three defining features of the syndrome
in which CUL3 variants were identified.
- reference: PMID:34480842
reference_title: "Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A 7-year-old boy had hypertension, metabolic acidosis, and persistent hyperkalemia, which were initially detected during the evaluation of short stature."
explanation: Documents hypertension in a genetically confirmed CUL3 patient.
- category: Laboratory
name: Hyperkalemia
frequency: VERY_FREQUENT
description: >-
Hyperkalaemia with a low transtubular potassium gradient, that is, a renal
rather than extrarenal cause, and a normal glomerular filtration rate. Its
origin is only partly explained by NCC activation and the ROMK hypothesis
was tested and not confirmed in the knock-in mouse.
phenotype_term:
preferred_term: Hyperkalemia
term:
id: HP:0002153
label: Hyperkalemia
evidence:
- reference: PMID:22266938
reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis"
explanation: Names hyperkalaemia as a defining feature of the syndrome.
- reference: PMID:34480842
reference_title: "Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Laboratory test findings showed hyperkalemia with low trans-tubular potassium gradient, hyperchloremic metabolic acidosis with a normal anion gap, and low plasma renin levels."
explanation: >-
Documents hyperkalaemia with the low transtubular potassium gradient that
localises the defect to the kidney.
- category: Laboratory
name: Hyperchloremic metabolic acidosis
frequency: FREQUENT
description: >-
Metabolic acidosis with a normal anion gap and raised chloride, reflecting
reduced distal hydrogen ion secretion alongside the chloride retained with
sodium by NCC.
phenotype_term:
preferred_term: Hyperchloremic metabolic acidosis
term:
id: HP:0004918
label: Hyperchloremic metabolic acidosis
sequelae:
- target: Growth delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Persistent acidosis is the mechanism proposed for the growth impairment,
and early correction is reported to preserve normal growth. The
intermediate steps between chronic acidosis and impaired growth are not
specified by the source.
evidence:
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Timely and accurate diagnosis of PHA2 is critical, as persistent metabolic acidosis and hypertension may lead to significant growth and developmental impairments in pediatric patients."
explanation: >-
Names persistent metabolic acidosis as a cause of growth impairment in
this disease, which is the edge drawn here.
evidence:
- reference: PMID:34480842
reference_title: "Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Laboratory test findings showed hyperkalemia with low trans-tubular potassium gradient, hyperchloremic metabolic acidosis with a normal anion gap, and low plasma renin levels."
explanation: >-
Documents hyperchloraemic metabolic acidosis with a normal anion gap in a
CUL3 patient, which is the specific acid-base pattern bound here.
- category: Laboratory
name: Decreased circulating renin concentration
frequency: FREQUENT
description: >-
Renin is suppressed by the volume expansion that salt retention produces.
Low renin with hyperkalaemia is the combination that distinguishes this
disease from the secondary hyperaldosteronism of salt-wasting states.
phenotype_term:
preferred_term: Decreased circulating renin concentration
term:
id: HP:0003351
label: Decreased circulating renin concentration
evidence:
- reference: PMID:34480842
reference_title: "Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Laboratory test findings showed hyperkalemia with low trans-tubular potassium gradient, hyperchloremic metabolic acidosis with a normal anion gap, and low plasma renin levels."
explanation: Documents low plasma renin in a genetically confirmed CUL3 patient.
- category: Laboratory
name: Decreased circulating aldosterone concentration
description: >-
This is the atypical finding, not the rule, and the entry carries it because
it is what produced a documented misdiagnosis. The usual report in
pseudohypoaldosteronism type 2 is a normal or high aldosterone alongside the
low renin, which is the paradox the disease name obscures: the kidney
behaves as though aldosterone were absent while it is not. One CUL3 patient
had aldosterone suppressed along with renin and was treated with
fludrocortisone for a presumed aldosterone deficiency. Both readings are
cited here, and no frequency is assigned because the two sources disagree on
direction.
phenotype_term:
preferred_term: Decreased circulating aldosterone concentration
term:
id: HP:0004319
label: Decreased circulating aldosterone concentration
evidence:
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "On referral, significant hypertension, hyperkalemia, and suppressed renin and aldosterone were observed."
explanation: >-
Documents suppressed aldosterone as well as renin in a CUL3 patient, the
finding behind the reported diagnostic pitfall.
- reference: PMID:27369102
reference_title: "[Gordon syndrome: The importance of measuring blood pressure in children]."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "The typical clinical picture of Gordon syndrome includes, apart from arterial hypertension and dyskaliemia, hyperchloremia metabolic acidosis, hypercalciuria, a low rate of renin, and most frequently, a normal or high rate of aldosterone."
explanation: >-
Contradicts a decreased-aldosterone reading as the general picture: this
source states that aldosterone is most frequently normal or high. Cited as
a refutation so the entry does not present the suppressed-aldosterone case
as typical.
- category: Laboratory
name: Hypercalciuria
description: >-
Raised urinary calcium is listed as part of the typical biochemical picture
of this disease. No edge is drawn from the pathograph to it: the obvious
reading is that activated NCC raises distal calcium excretion, the mirror of
the hypocalciuria thiazides cause, but neither source cited here states that
mechanism, so the link is left unasserted rather than inferred.
phenotype_term:
preferred_term: Hypercalciuria
term:
id: HP:0002150
label: Hypercalciuria
evidence:
- reference: PMID:27369102
reference_title: "[Gordon syndrome: The importance of measuring blood pressure in children]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The typical clinical picture of Gordon syndrome includes, apart from arterial hypertension and dyskaliemia, hyperchloremia metabolic acidosis, hypercalciuria, a low rate of renin, and most frequently, a normal or high rate of aldosterone."
explanation: >-
Names hypercalciuria as part of the typical biochemical constellation of
the disease.
- category: Clinical
name: Growth delay
description: >-
Impaired growth is reported as an associated feature, and in one CUL3 case
it was the finding that, together with hyperkalaemia and acidosis, pointed
to the diagnosis. Persistent metabolic acidosis is the proposed driver, so
the entry draws the edge from the acidosis rather than from the hypertension.
Related to but distinct from the Short stature entry, which records a
measured stature outcome in a different patient.
phenotype_term:
preferred_term: Growth delay
term:
id: HP:0001510
label: Growth delay
sequelae:
- target: Short stature
causal_link_type: DIRECT
description: >-
Short stature is the measured outcome of sustained growth delay. The edge
carries no citation of its own because no source cited here asserts it:
the relation between a reduced growth rate and a subnormal final stature
is definitional rather than a finding about this disease.
evidence:
- reference: PMID:27369102
reference_title: "[Gordon syndrome: The importance of measuring blood pressure in children]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dental abnormalities and growth retardation can also be associated."
explanation: >-
Lists growth retardation among the features associated with this disease.
- reference: PMID:27369102
reference_title: "[Gordon syndrome: The importance of measuring blood pressure in children]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The association of growth retardation, hyperkaliemia, and metabolic acidosis oriented the diagnosis."
explanation: >-
Documents growth retardation in the authors' own CUL3 patient, and its
role in reaching the diagnosis.
- category: Clinical
name: Abnormality of the dentition
description: >-
Dental abnormalities are named as an associated feature of the disease. The
source does not say which dental abnormality, so the binding stays at the
general term rather than being narrowed to a specific defect, and no causal
edge is drawn because no mechanism connecting the renal defect to the teeth
is described in any source cited here.
phenotype_term:
preferred_term: Abnormality of the dentition
term:
id: HP:0000164
label: Abnormality of the dentition
evidence:
- reference: PMID:27369102
reference_title: "[Gordon syndrome: The importance of measuring blood pressure in children]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dental abnormalities and growth retardation can also be associated."
explanation: >-
Names dental abnormalities among the features associated with this
disease, without specifying which.
- category: Clinical
name: Short stature
description: >-
Short stature has been the presenting complaint in a CUL3 patient, in whom
growth hormone testing was normal and stature remained short after thiazide
treatment normalised the electrolytes. Persistent metabolic acidosis is the
proposed mechanism. Growth outcome is not uniform: another CUL3 child
treated with low-dose thiazide from age 2 had normal growth on long-term
follow-up, so this is a recognised but not obligate feature.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:34480842
reference_title: "Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GS should be considered in children with short stature, hypertension, and hyperkalemia, and early treatment may reduce complications."
explanation: >-
The authors' conclusion that short stature belongs to the presenting
picture of this disease in children.
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Timely and accurate diagnosis of PHA2 is critical, as persistent metabolic acidosis and hypertension may lead to significant growth and developmental impairments in pediatric patients."
explanation: >-
Supports the mechanism proposed for the growth impairment, persistent
acidosis and hypertension, and that it is avoidable with early treatment.
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "Long-term follow-up confirmed clinical stability, normal growth, and appropriate developmental milestones."
explanation: >-
Records the counter-case, a CUL3 patient treated early who grew normally.
Cited against an obligate reading of this phenotype, which is why no
frequency is assigned.
- category: Clinical
name: Vomiting
description: >-
Recurrent vomiting was the presenting symptom in an early-onset CUL3 case at
2 years 7 months, before hypertension was recognised. No causal edge is
drawn to it: the source reports the vomiting and the electrolyte
abnormalities together without stating that one produced the other, and
vomiting in a child with hyponatraemia has several candidate explanations.
phenotype_term:
preferred_term: Vomiting
term:
id: HP:0002013
label: Vomiting
evidence:
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient, first evaluated at 2 years and 7 months of age for recurrent vomiting, was found to have hyponatremia, hyperkalemia, and metabolic acidosis, initially treated with fludrocortisone."
explanation: Documents recurrent vomiting as the presenting symptom in a CUL3 patient.
progression:
- phase: Early-onset presentation in childhood
age_range: Early childhood to school age
notes: >-
The CUL3 subtype presents earlier and more severely than the WNK and KLHL3
subtypes. Reported presentations include recurrent vomiting at 2 years 7
months and incidental detection during evaluation of short stature at 7
years. The electrolyte disturbance is often found before the hypertension is
recognised, and misdiagnosis as an aldosterone deficiency state is
documented.
evidence:
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "While FHHt patients with CUL3, KLHL3 or WNK mutations present with the same disease, those with mutations in CUL3 display a more severe phenotype, evident in terms of both an earlier age-of-onset and the degree of hypertension and electrolyte disturbance reported"
explanation: >-
States the earlier onset and greater severity of the CUL3 subtype against
its siblings. The sentence is this paper's background synthesis of three
human clinical reports it cites, not its own mouse or biochemical data,
so the evidence described is human clinical and the quote role is
background.
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Pathogenic variants in WNK1, WNK4, KLHL3, and CUL3 have been identified, with CUL3 mutations particularly associated with early-onset and severe phenotypes."
explanation: >-
Independently states the early-onset and severe character of the CUL3
subtype. Quoted from the framing section of a case report rather than from
its own case data.
- reference: PMID:31813255
reference_title: "Hypertension-causing cullin 3 mutations disrupt COP9 signalosome binding."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The CUL3 FHHt mutations cause the most severe phenotype, yet the precise mechanism by which these mutations cause the disease has not been established and current proposed models are controversial."
explanation: >-
A third independent statement that the CUL3 subtype is the most severe,
from a review of the mechanism literature. The same sentence records that
the mechanism behind that severity is unsettled.
biochemical:
- name: Serum potassium
notes: >-
Elevated, with a low transtubular potassium gradient indicating reduced
renal potassium secretion rather than an extrarenal cause, and with a normal
glomerular filtration rate.
biomarker_term:
preferred_term: Potassium
term:
id: NCIT:C765
label: Potassium
presence: INCREASED
evidence:
- reference: PMID:34480842
reference_title: "Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Laboratory test findings showed hyperkalemia with low trans-tubular potassium gradient, hyperchloremic metabolic acidosis with a normal anion gap, and low plasma renin levels."
explanation: >-
Reports the potassium abnormality together with the gradient that
interprets it.
- name: Plasma renin
notes: >-
Suppressed, despite hyperkalaemia, because salt retention expands volume.
This combination is what separates the disease biochemically from
salt-wasting pseudohypoaldosteronism type 1, where renin is high.
biomarker_term:
preferred_term: Renin
term:
id: NCIT:C113591
label: Renin
presence: DECREASED
evidence:
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "On referral, significant hypertension, hyperkalemia, and suppressed renin and aldosterone were observed."
explanation: Reports suppressed renin in a CUL3 patient.
diagnosis:
- name: Molecular genetic testing of CUL3
description: >-
Next-generation sequencing establishes the diagnosis and the subtype.
Because every PHA2E allele acts by exon 9 skipping and the variants that do
so include deep intronic and synonymous changes, a protein-level
interpretation can miss them, and a splicing readout on patient RNA is the
confirmatory step where the variant is not a canonical splice-site change.
evidence:
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Next generation sequencing has emerged as a valuable tool for establishing a definitive diagnosis, particularly in cases with aldosterone defects."
explanation: Supports sequencing as the route to a definitive diagnosis here.
- reference: PMID:29511623
reference_title: "A novel mutation in exon 9 of Cullin 3 gene contributes to aberrant splicing in pseudohypoaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "explored its effects on exon 9 abnormal splicing through an in vitro splicing assay and study of the patients' RNA"
explanation: >-
Describes the splicing readout on patient RNA that was needed to call a
synonymous variant pathogenic.
- name: Biochemical profile of hyperkalemia with suppressed renin
description: >-
Hyperkalaemia and hyperchloraemic metabolic acidosis with suppressed renin,
preserved renal function and hypertension. The pattern is easily misread:
one reported child was treated with fludrocortisone for a presumed
aldosterone deficiency before the hypertension was weighed.
evidence:
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Aldosterone pathway defects may be misdiagnosed during the initial clinical assessment. This underscores the importance of a comprehensive diagnostic approach incorporating biochemical profiling and genetic testing to ensure accurate identification."
explanation: >-
Supports both the role of biochemical profiling and the documented risk of
misdiagnosis at first assessment.
treatments:
- name: Thiazide diuretic
therapeutic_modality: SMALL_MOLECULE
description: >-
Low-dose thiazide inhibits NCC, the overactive transporter at the end of the
disease mechanism, and corrects both the electrolyte disturbance and the
blood pressure. This is a mechanism-matched treatment rather than a
symptomatic one, and the response is part of the diagnostic picture.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: thiazide diuretic
term:
id: NCIT:C49185
label: Thiazide Diuretic
target_mechanisms:
- target: NCC Phosphorylation and Overactivity
description: >-
Thiazides inhibit the Na-Cl cotransporter directly, which is the node this
treatment acts on.
evidence:
- reference: PMID:22266938
reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney"
explanation: >-
States both that thiazides reverse the disease features and that they
act on the Na-Cl cotransporter, which is the mechanism link asserted
here.
evidence:
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Initiation of low-dose thiazide therapy led to normalization of blood pressure and electrolytes."
explanation: >-
Documents normalisation of both blood pressure and electrolytes on
low-dose thiazide in a CUL3 patient.
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Despite the potential severity of clinical manifestations associated with CUL3-related PHA2, it is noteworthy that treatment with thiazide diuretics alone can effectively restore electrolyte balance and support normal growth and development."
explanation: >-
Supports thiazide monotherapy as sufficient in CUL3-related disease
specifically, including for growth.
- reference: PMID:34480842
reference_title: "Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "After thiazide treatment, the patient's electrolyte levels were normalized. However, he presented with persistent hypertension and short stature."
explanation: >-
Records an incomplete response, electrolytes corrected while hypertension
and short stature persisted in a child treated from age 7.
- reference: PMID:27369102
reference_title: "[Gordon syndrome: The importance of measuring blood pressure in children]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Starting a thiazide diuretic helped control the arterial hypertension and the kaliemia in a spectacular manner."
explanation: >-
A third CUL3 patient in whom thiazide controlled both the hypertension and
the potassium, in the authors' own case.
- reference: PMID:27369102
reference_title: "[Gordon syndrome: The importance of measuring blood pressure in children]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "it is important to diagnose this syndrome because of the spectacular efficacy of thiazide diuretics"
explanation: >-
States that the size of the thiazide response is itself the reason the
diagnosis matters clinically.
- name: Dietary salt restriction
therapeutic_modality: BEHAVIORAL
description: >-
The hypertension is salt-dependent, so reducing dietary salt reduces the
substrate for the overactive cotransporter. Reported as effective alone or
alongside thiazide.
treatment_term:
preferred_term: Dietary Intervention
term:
id: NCIT:C15447
label: Dietary Intervention
target_mechanisms:
- target: Increased Distal Nephron Salt Reabsorption
description: >-
Limiting sodium intake limits the sodium available for the overactive
distal reabsorption this node describes.
evidence:
- reference: PMID:24266877
reference_title: "Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "is effectively treated by thiazide diuretics and/or dietary salt restriction"
explanation: >-
States that dietary salt restriction is an effective treatment for this
disease, alone or with thiazide.
animal_models:
- name: CUL3 exon 9 deletion knock-in mouse
species: Mouse
genotype: Cul3 WT/delta403-459 heterozygous knock-in
publication: PMID:26286618
description: >-
A heterozygous knock-in carrying the same in-frame exon 9 deletion found in
patients. It reproduces the human electrolyte and blood pressure phenotype
and, unlike earlier WNK and KLHL3 models, also shows arterial pulse waveform
changes, which is the finding that put a vascular component into the
mechanism. An independently generated knock-in of the same deletion
reproduces the phenotype and the KLHL3 fall.
genes:
- preferred_term: CUL3
term:
id: hgnc:2553
label: CUL3
modeled_mechanisms:
- target: CUL3 Exon 9 Skipping
relationship: RECAPITULATES
fidelity: HIGH
model_scale: MOLECULAR
description: >-
The knock-in carries the identical in-frame deletion, so the initiating
lesion is the same molecular event as in patients rather than a
surrogate.
evidence:
- reference: PMID:29869755
reference_title: "Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "we generated and analyzed knock-in mice carrying the same CUL3 exon9 deletion (CUL3WT/Δex9) as that reported in PHAII patients."
explanation: >-
States that the engineered allele is the same exon 9 deletion reported
in patients.
- target: KLHL3 Depletion
relationship: RECAPITULATES
fidelity: HIGH
model_scale: MOLECULAR
description: >-
The in vivo confirmation that KLHL3 abundance falls, which cell-based work
had predicted.
evidence:
- reference: PMID:29869755
reference_title: "Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Interestingly, we confirmed markedly decreased KLHL3 expression in CUL3WT/Δex9 mice by confirming the true KLHL3 band in vivo."
explanation: Reports the KLHL3 fall in the knock-in mouse kidney.
- target: Impaired Vasodilation and Enhanced Vasoconstriction
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
limitations: >-
The model's vascular readout is an arterial pulse waveform change, which
is a whole-animal haemodynamic measure. It is consistent with altered
vascular tone but does not itself measure vasodilator or vasoconstrictor
responses, and the authors state it as a suggestion rather than a
demonstration. No equivalent human vascular measurement is reported.
divergences:
- divergence_type: PROXY_QUANTITY
materiality: QUALIFYING
description: >-
The measured quantity is the arterial pulse waveform of the intact
mouse. The node's quantity is vasodilator and vasoconstrictor function
of vascular smooth muscle. The waveform is a downstream composite of
tone, stiffness and cardiac output rather than a measurement of
dilation.
evidence:
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models."
explanation: >-
The vascular finding in this model, reported by the authors as
suggestive of a vascular contribution.
evidence:
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "A novel knock-in mouse model of CUL3(WT) (/Δ403-459) closely recapitulates the human PHA2E phenotype."
explanation: >-
Supports treating this model as informative for the human disease, in the
authors' own assessment.
- name: Nephron-specific Cul3 knockout mouse
species: Mouse
genotype: Nephron-specific Cul3 deletion
publication: PMID:25250572
description: >-
A conditional deletion used to test whether losing cullin-3 activity in the
nephron phenocopies the disease. It reproduces the proximal part of the
mechanism, raising WNK kinase levels and phosphorylated NCC, but then
diverges: over time the mice develop hypochloraemic alkalosis, diabetes
insipidus, salt-sensitive hypotension, renal inflammation and fibrosis. The
divergence is informative rather than a failure of the model, because it is
what shows that the human disease is not a simple nephron loss of cullin-3
function.
genes:
- preferred_term: CUL3
term:
id: hgnc:2553
label: CUL3
modeled_mechanisms:
- target: WNK Kinase Accumulation
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: MOLECULAR
limitations: >-
A complete nephron deletion, not the in-frame deletion patients carry, and
patients retain one wild-type allele. The same paper shows WNK4
degradation is restored when wild-type cullin-3 is present, so the
heterozygous human state is not reproduced by the null.
evidence:
- reference: PMID:25250572
reference_title: "Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "As predicted, nephron-specific deletion of Cul3 in mice did increase WNK kinase levels and the abundance of phosphorylated Na-Cl cotransporter (NCC)."
explanation: >-
Reports the predicted rise in WNK kinase levels in the nephron-specific
knockout.
- target: Increased Distal Nephron Salt Reabsorption
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
model_scale: ORGANISM
limitations: >-
Instead of the salt retention and hypertension of the human disease, these
mice end up with salt-sensitive hypotension, hypochloraemic alkalosis and
diabetes insipidus, with renal inflammation and fibrosis. Removing
cullin-3 entirely from the nephron is toxic in ways the patient allele is
not, so this model cannot stand in for the disease at the physiological
level.
evidence:
- reference: PMID:25250572
reference_title: "Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: "Over time, however, Cul3 deletion caused renal dysfunction, including hypochloremic alkalosis, diabetes insipidus, and salt-sensitive hypotension, with depletion of sodium potassium chloride cotransporter 2 and aquaporin 2."
explanation: >-
Records the opposite physiological outcome to the human disease, which
is why this link is a failure to recapitulate rather than a partial one.
evidence:
- reference: PMID:25250572
reference_title: "Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "whereas general loss of CUL3 activity - while also impairing WNK degradation - has widespread toxic effects in the kidney."
explanation: >-
The authors' own summary of why the null model separates from the disease,
which is what this model entry is informative for.
differential_diagnoses:
- name: Neurodevelopmental disorder with or without autism or seizures (CUL3-related)
disease_term:
preferred_term: neurodevelopmental disorder with or without autism or seizures
term:
id: MONDO:0030994
label: neurodevelopmental disorder with or without autism or seizures
description: >-
The same gene and the same inheritance, separated by variant class rather
than by dose. Loss-of-function CUL3 variants distributed across the gene
cause a neurodevelopmental disorder with no electrolyte abnormality, while
the variants here converge on exon 9 skipping and produce a stable mutant
protein. ClinGen split the two concepts explicitly on the grounds of
differing molecular mechanism and clinical phenotype, and curated them in
separate expert panels. A CUL3 variant report therefore has to be read for
variant class before it is read for gene identity. The boundary is not
absolute: the largest neurodevelopmental cohort noted individuals with early
or juvenile-onset hypertension without electrolyte abnormalities.
distinguishing_features:
- Convergence of all alleles on exon 9 skipping, versus truncating, splice and
missense alleles distributed across the gene
- Hyperkalaemia and hyperchloraemic metabolic acidosis, absent in the
neurodevelopmental disorder
- Thiazide-responsive hypertension as the presenting problem rather than
developmental delay
- No intellectual disability, speech delay or autism
evidence:
- reference: CGGV:assertion_f697fb5e-72de-4116-9cad-706e2d651268-2021-12-01T013000.000Z
reference_title: "CUL3 / pseudohypoaldosteronism type 2E (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "Per criteria outlined by the ClinGen Lumping and Splitting Working Group, although both conditions have an AD inheritance, there is a difference in molecular mechanism and in clinical phenotype."
explanation: >-
ClinGen's recorded reason for treating these as two distinct disease
entities, which is the basis for curating them as separate dismech
entries.
- reference: PMID:22266938
reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion."
explanation: >-
Establishes the allele class that separates this disease from the
loss-of-function neurodevelopmental disorder.
- name: Pseudohypoaldosteronism type 2D (KLHL3-related)
disease_term:
preferred_term: pseudohypoaldosteronism type 2D
term:
id: MONDO:0013781
label: pseudohypoaldosteronism type 2D
description: >-
The adjacent subtype, caused by variants in the substrate adaptor that
CUL3-delta9 depletes, so the two converge on the same failure of WNK
degradation and are clinically indistinguishable feature by feature. They
separate on inheritance pattern and on severity: KLHL3 alleles are recessive
or dominant where CUL3 alleles are dominant and usually de novo, and the
CUL3 subtype presents earlier and more severely.
distinguishing_features:
- KLHL3 alleles may be recessive or dominant; CUL3 alleles are dominant and
predominantly de novo
- Earlier age of onset and greater hypertension and electrolyte disturbance in
the CUL3 subtype
evidence:
- reference: PMID:22266938
reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo."
explanation: >-
States the inheritance difference between the two subtypes, which is one
of the two discriminators.
- reference: PMID:26286618
reference_title: "Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "While FHHt patients with CUL3, KLHL3 or WNK mutations present with the same disease, those with mutations in CUL3 display a more severe phenotype, evident in terms of both an earlier age-of-onset and the degree of hypertension and electrolyte disturbance reported"
explanation: >-
States the severity difference against the KLHL3 and WNK subtypes.
Background synthesis of the human reports it cites rather than this
paper's own data.
- name: Pseudohypoaldosteronism type 1 (ENaC and NR3C2-related)
disease_term:
preferred_term: pseudohypoaldosteronism type 1
term:
id: MONDO:0019161
label: pseudohypoaldosteronism type 1
description: >-
Shares hyperkalaemia and metabolic acidosis but is the mirror image
physiologically: renal salt wasting with hypovolaemia and markedly elevated
renin and aldosterone, rather than salt retention with hypertension and
suppressed renin. Blood pressure and renin separate them immediately, and
treatment is opposite, sodium supplementation rather than a thiazide. The
distinction matters because a child presenting with hyperkalaemia and
acidosis can be started on fludrocortisone for a presumed aldosterone
deficiency, which is documented in a CUL3 patient.
distinguishing_features:
- Hypertension with suppressed renin, versus hypovolaemia with elevated renin
and aldosterone
- Thiazide and salt restriction, versus sodium and bicarbonate supplementation
evidence:
- reference: PMID:41380172
reference_title: "Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient, first evaluated at 2 years and 7 months of age for recurrent vomiting, was found to have hyponatremia, hyperkalemia, and metabolic acidosis, initially treated with fludrocortisone."
explanation: >-
Documents the actual misdiagnosis this differential guards against, a CUL3
patient treated as an aldosterone deficiency state.
- reference: PMID:41982973
reference_title: "Clinical and molecular characteristics of a series of Chinese children with pseudohypoaldosteronism: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Management was tailored to the subtype, including aggressive salt supplementation for systemic PHAI and thiazide diuretics for PHAII."
explanation: >-
States the opposite management of the two types, which is why the
distinction is clinically consequential.
discussions:
- discussion_id: cul3_delta9_neddylation_direction
kind: CONTROVERSY
status: OPEN
posed_by: "dismech curation"
prompt: >-
Is CUL3-delta9 hyperneddylated and over-activated, or under-neddylated and
under-activated, and does the answer change what the dominant mechanism in
patients is?
rationale: >-
Two cell-based studies report opposite directions for the same
modification on the same mutant protein. McCormick et al. report that
CUL3-delta9 is more heavily neddylated and more activated than wild-type,
with the disease arising because that over-active ligase destroys its own
adaptor KLHL3. Ibeawuchi et al. report that neddylation of the same mutant
and its binding to RBX1 are both significantly impaired, with the disease
arising because the mutant sequesters adaptors and poisons wild-type dimers.
Cornelius et al. set out to resolve it, name hyperneddylation as one of
several postulated mechanisms, and conclude for a protein that is itself
ligase-defective while driving autophagic KLHL3 degradation. The two
accounts are not merely different emphases: they disagree on the sign of the
measured modification. Both are compatible with the clinical phenotype
because both end in failed WNK degradation, which is why the disagreement
has persisted without being decisive for diagnosis or treatment. It matters
for anything that would target the pathway pharmacologically, since a
neddylation inhibitor would be expected to act in opposite directions under
the two models.
attaches_to:
- pathophysiology#Loss of CUL3-delta9 Interaction with Cullin Regulators
- pathophysiology#CUL3-delta9 Ubiquitin Ligase Dysfunction
evidence:
- reference: PMID:25250572
reference_title: "Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Here, we demonstrated that an FHHt-causing CUL3 mutant (CUL3 Δ403-459) not only retains the ability to bind and ubiquitylate WNK kinases and KLHL3 in cells, but is also more heavily neddylated and activated than WT CUL3."
explanation: >-
One side of the disagreement, that the mutant is more heavily neddylated
and more active than wild-type.
- reference: PMID:26100637
reference_title: "Hypertension-causing Mutations in Cullin3 Protein Impair RhoA Protein Ubiquitination and Augment the Association with Substrate Adaptors."
supports: REFUTE
evidence_source: IN_VITRO
snippet: "Consistent with its reduced activity, binding of Cul3Δ9 to the E3 ubiquitin ligase Rbx1 and neddylation of Cul3Δ9 were impaired significantly compared with Cul3WT."
explanation: >-
The other side, that neddylation of the same mutant is significantly
impaired rather than increased. Cited as refuting the hyperneddylation
reading.
- reference: PMID:29897280
reference_title: "Dual gain and loss of cullin 3 function mediates familial hyperkalemic hypertension."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Although the mechanisms by which WNK and KLHL3 mutations cause the disease are now clear, the effects of the disease-causing CUL3Δ403-459 mutation remain controversial."
explanation: >-
An independent statement that the mechanism is unresolved, which is what
makes this a recorded controversy rather than a settled node.
- reference: PMID:31813255
reference_title: "Hypertension-causing cullin 3 mutations disrupt COP9 signalosome binding."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "New data have identified a possible novel mechanism involving dysregulation of CUL3 activity by the COP9 signalosome (CSN). The CSN interaction with mutant CUL3 is diminished, causing hyperneddylation of the CRL."
explanation: >-
A dedicated review of this question, taking the hyperneddylation side via
loss of COP9 signalosome binding and describing it as a possible mechanism
rather than a settled one. Records where the field stood when the review
was written.
- discussion_id: pha2e_hyperkalemia_origin
kind: KNOWLEDGE_GAP
status: OPEN
posed_by: "dismech curation"
prompt: >-
What accounts for the part of the hyperkalaemia in PHA2E that NCC
activation does not explain, given that reduced ROMK expression was tested
in the knock-in mouse and not found?
rationale: >-
The hypertension in this disease follows cleanly from NCC activation, but
the hyperkalaemia does not. Two sources state that the electrolyte
abnormalities are only partly driven by NCC. The obvious candidate was
reduced expression of the distal secretory potassium channel ROMK, and that
was the explicit target of a dedicated study: CUL3-delta9 did fail to
prevent WNK4 suppression of ROMK currents in oocytes and did not support
ROMK surface expression in collecting duct cells, yet in the knock-in mouse
no change in ROMK expression could be shown by western blotting or confocal
microscopy. So the in vitro result did not transfer to the animal, and the
residual mechanism is unidentified. This is a gap rather than a controversy
because no competing positive account has been offered.
attaches_to:
- phenotypes#Hyperkalemia
- pathophysiology#Increased Distal Nephron Salt Reabsorption
evidence:
- reference: PMID:27378813
reference_title: "ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "This accounts for the hypertension in FHHt but the origin of the hyperkalemia is less clear."
explanation: >-
States the gap directly, that NCC activation explains the hypertension but
not the hyperkalaemia.
- reference: PMID:27378813
reference_title: "ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "This suggests that the hyperkalemia in our knock-in mouse and human PHA2E subjects with the CUL3(Δ403-459) mutation is not caused by reduced ROMK expression in the distal nephron."
explanation: >-
The negative result that closes off the leading candidate explanation and
leaves the gap open.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Pseudohypoaldosteronism Type 2E (CUL3) · 2026-10-30T16:22:04Z · View source
Created the CUL3 form of familial hyperkalaemic hypertension as a Disease entry (entry_type DISEASE). ClinGen's Tubulopathy GCEP record (CGGV:assertion_f697fb5e-...) classifies CUL3 to PHA2E as Definitive and states that the ClinGen Lumping and Splitting Working Group split PHA2E from the CUL3 neurodevelopmental disorder on differing molecular mechanism and clinical phenotype, which is the basis for curating it separately from kb/disorders/Neurodevelopmental_Disorder_With_or_Without_Autism_or_Seizures.yaml. That entry already listed PHA2E as a differential; this entry mirrors the link. Pathograph: a ten-node chain from CUL3 exon 9 skipping through loss of COP9 signalosome and CAND1 interaction, ligase dysfunction, KLHL3 depletion, WNK accumulation, SPAK/OSR1 activation and NCC overactivity to distal salt reabsorption, plus a parallel vascular arm (RhoA accumulation in vascular smooth muscle to impaired vasodilation). Six of ten phenotypes are causally wired. Four are deliberately left isolated with the reason recorded in each description: hypercalciuria (the NCC-mediated calcium mechanism is plausible but unstated by any cited source), dental abnormality (no mechanism described), vomiting (co-occurrence only), and decreased aldosterone (direction disputed). Two disagreements are recorded rather than resolved. The neddylation direction of CUL3-delta9 is a CONTROVERSY discussion: PMID:25250572 reports it more heavily neddylated and activated, PMID:26100637 reports neddylation and RBX1 binding significantly impaired, and PMID:29897280 and PMID:31813255 both call the mechanism unsettled. The origin of the hyperkalaemia is a KNOWLEDGE_GAP discussion: PMID:27378813 states NCC activation does not account for it and reports that the leading ROMK candidate was tested in the knock-in mouse and not found. functional_impact_category is DOMINANT_NEGATIVE on the cell-based evidence; the ClinGen record's own loss-of-function wording is noted on the validity assertion rather than overwritten. Aldosterone needed correcting during curation. An early draft carried decreased aldosterone on the strength of one case report; PMID:27369102 states aldosterone is most frequently normal or high, so that phenotype now carries both readings (SUPPORT and REFUTE) and no frequency, and the entry notes that the disease name misleads on this point. Deep research: research/Pseudohypoaldosteronism_Type_2E-deep-research-openscientist.md (openscientist, 24 min). reference_validation 21/21 resolved, 0 unresolved, confabulation_rate 0.0, 18/21 weighed on topic, 0 off topic. term_validation 22/23 verified with 5 label mismatches, one of which is substantive: the report offered HP:0004879 for hyperchloraemic metabolic acidosis, which HPO calls Intermittent hyperventilation. That term was not bound; HP:0004918 Hyperchloremic metabolic acidosis was looked up and used instead. just preflight-dr returned PASS (CUL3 mentioned 90 times, OMIM 614496 matching MONDO). The report supplied PMID:27369102 and PMID:31813255, which added hypercalciuria, dental abnormality, growth delay and the aldosterone correction. Three CURIEs written from memory in a first draft were caught by the pre-edit validation hook and replaced with looked-up values: NCIT:C2296 (Progestogen, not Renin) became NCIT:C113591; MONDO:0030879 does not exist and became MONDO:0030994 for the neurodevelopmental disorder, read from the committed entry; MONDO:0018962 (common mesentery) became MONDO:0019161 for pseudohypoaldosteronism type 1. just check-gene-activity-grounding then flagged CUL3 landing on a node with no molecular function; GO:0160072 ubiquitin ligase complex scaffold activity was taken from the ai-gene-review ingest table and bound without a modifier, because the direction is what the literature disputes. No GeneReviews or StatPearls chapter exists (just check-genereviews --online, NO_CHAPTER on both lines with five synonyms present). Validation run: just validate, just validate-terms, just count-verified-snippets (92/92), just validate-disorders (92 snippets, 98 titles, 0 issues), check-folded-hyphens, check-folded-yaml, check-snippet-length, check-title-snippets, check-reference-titles, check-retired-support-prose, check-environmental-evidence, check-snippet-grading, check-shared-disease-terms, check-case-collisions, check-gene-activity-grounding, check-duplicate-keys, check-block-scalar-comments, check-enum-values, check-delivery-system, check-entity-refs, check-logical-rules, check-causal-targets, check-coarse-phenotypes, check-qualifier-terms, list-gene-term-mismatches, normalize-cache, check-term-cache-integrity. All passed.
PHA2E is a rare inherited monogenic form of low-renin hypertension within the FHHt/Gordon syndrome/PHAII spectrum. It is defined molecularly by its causal gene, CUL3 (cullin-3), which distinguishes it from the other PHAII subtypes caused by WNK1 (PHA2C), WNK4 (PHA2B), and KLHL3 (PHA2D).
Key identifiers:
| Resource | Identifier |
|---|---|
| MONDO | MONDO:0013782 |
| OMIM | 614496 (PSEUDOHYPOALDOSTERONISM, TYPE IIE; PHA2E) |
| Causal gene | CUL3 (HGNC:2553; NCBI Gene 8452; chromosome 2q36.2) |
| Disease family | Familial hyperkalemic hypertension (FHHt) / Gordon syndrome / PHAII |
Synonyms and alternative names: pseudohypoaldosteronism type 2 caused by mutation in CUL3; CUL3 pseudohypoaldosteronism type 2; PHA2E; Gordon syndrome (CUL3-related); familial hyperkalemic hypertension, CUL3 type.
Information source: The disease-level characterization here derives principally from aggregated disease-level resources (OMIM, published case series, and mechanistic studies) combined with individual patient case reports. PHA2E is sufficiently rare that no large patient-level EHR registries exist specifically for the CUL3 subtype; evidence comes from case reports, small pedigree studies, and mechanistic mouse/cell models.
Primary cause — genetic. PHA2E is caused by heterozygous, dominant, predominantly de novo mutations in CUL3. Boyden et al. (2012) used exome sequencing across 41 unrelated PHAII families to identify CUL3 (and KLHL3) as causal genes: "KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo" (PMID: 22266938). A key convergent feature is that diverse CUL3 mutations — spanning splice-donor and splice-acceptor sites flanking exon 9 — all produce the same outcome: "Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion" (PMID: 22266938).
Genetic risk factors. The causal variants are the CUL3 exon-9 splice-site mutations themselves. There are no known common susceptibility loci or modifier alleles established specifically for PHA2E; the disorder is monogenic with high penetrance.
Environmental risk factors. Dietary sodium (salt) load worsens the hypertensive phenotype because the underlying defect is excessive renal NaCl reabsorption; dietary potassium load exacerbates hyperkalemia. These are modifiers of expression rather than causes.
Protective factors. Dietary sodium restriction is a protective/ameliorating environmental factor, reducing the substrate for NCC-driven NaCl retention. No genetic protective variants are established.
Gene-environment interactions. The core interaction is between the CUL3 genotype (which fixes NCC in a hyperactive state) and dietary salt and potassium intake, which determine the magnitude of hypertension and hyperkalemia. Co-occurrence of a second channelopathy variant can modify phenotype — a notable case reported a girl carrying both SCNN1A (PHAI) and CUL3 (PHAII) mutations, producing a complex mixed salt-handling phenotype (PMID: 36303414).
The core phenotype is a biochemical and hemodynamic constellation. Bruel et al. (2016) summarize the typical picture: "The typical clinical picture of Gordon syndrome includes, apart from arterial hypertension and dyskaliemia, hyperchloremia metabolic acidosis, hypercalciuria, a low rate of renin, and most frequently, a normal or high rate of aldosterone. Dental abnormalities and growth retardation can also be associated" (PMID: 27369102).
| Phenotype | Type | HPO term (suggested) | Characteristics |
|---|---|---|---|
| Arterial hypertension | Clinical sign | HP:0000822 (Hypertension) | Childhood-onset possible; severe in CUL3; the defining feature |
| Hyperkalemia | Laboratory abnormality | HP:0002153 | Present despite normal GFR; can be life-threatening |
| Hyperchloremic metabolic acidosis | Laboratory abnormality | HP:0004879 / HP:0001947 | Characteristic of PHAII |
| Hypercalciuria | Laboratory abnormality | HP:0002150 | Associated finding |
| Suppressed plasma renin | Laboratory abnormality | — (low renin) | Low renin is diagnostic |
| Normal/high aldosterone | Laboratory abnormality | — | Distinguishes from true hypoaldosteronism |
| Growth retardation | Physical manifestation | HP:0001510 (Growth delay) | In pediatric cases, linked to persistent acidosis/hypertension |
| Dental abnormalities | Physical manifestation | HP:0000164 (Abnormality of the teeth) | Reported association in Gordon syndrome |
| Short stature | Physical manifestation | HP:0004322 | Reported in some cases |
Age of onset: CUL3/PHA2E tends to present earlier and more severely than other FHHt subtypes — often in childhood. A representative CUL3 case was a 7-year-old girl with hypertension, growth retardation, hyperkalemia and metabolic acidosis carrying a de novo exon-9 splice mutation (PMID: 27369102).
Severity: CUL3 produces the most severe form of FHHt (PMID: 29361671).
Progression: Chronic and lifelong, but highly responsive to treatment. Untreated, persistent metabolic acidosis and hypertension may lead to significant growth and developmental impairments in pediatric patients (PMID: 41380172).
Frequency / quality of life: Hypertension and the biochemical triad are present in essentially all affected individuals; growth retardation and dental abnormalities are variable associations. With appropriate thiazide therapy, quality of life is largely preserved; untreated disease impairs growth/development and carries cardiac arrhythmia risk from hyperkalemia.
Causal gene: CUL3 (cullin-3), HGNC:2553, NCBI Gene 8452, located at chromosome 2q36.2. OMIM gene entry 603136; disease entry 614496.
Pathogenic variants. The pathognomonic lesion is skipping of exon 9, caused by heterozygous mutations at the intron 8 / exon 9 splice-acceptor site and the exon 9 / intron 9 splice-donor site, as well as some exonic variants. All converge on an in-frame deletion of 57 amino acids (residues 403-459): CUL3Δ403-459 (PMID: 22266938; PMID: 27378813).
Why CUL3 is more severe. The same study notes: "These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases" (PMID: 26286618). Loss of COP9-signalosome (CSN) binding is central — the catalytically active CSN subunit JAB1 fails to associate with the deleted CUL3 4-helix bundle domain (PMID: 29897280), and disrupted CSN binding has been confirmed as a major contributor to the FHHt phenotype in a renal CSN-deficient mouse (PMID: 30301860; see also PMID: 31813255).
Modifier genes: Within the pathway, the levels/activity of WNK1, WNK4, KLHL3, SPAK, OSR1, and NCC (SLC12A3) modulate the net phenotype. No formal modifier loci are established for PHA2E.
Epigenetic information: No disease-specific DNA methylation or histone modification signatures have been established for PHA2E. (CUL3 itself regulates protein stability of many substrates via ubiquitination/neddylation — a post-translational rather than epigenetic mechanism.)
Chromosomal abnormalities: None characteristic; PHA2E is a single-gene splice-defect disorder, not a copy-number or structural disorder.
PHA2E is a genetic disorder; environmental factors modulate expression rather than cause disease.
CUL3 splice mutation
│ (exon 9 skipping)
▼
CUL3Δ403-459 ── loses CSN/CAND1 binding, auto-ubiquitylates (gain + loss of function)
│
▼ (ligase fails to ubiquitinate WNKs)
WNK1 / WNK4 kinases accumulate (degradation abrogated)
│
▼ (phosphorylation)
SPAK / OSR1 overactivated
│
┌───┴──────────────────────────┐
▼ (renal DCT) ▼ (vascular smooth muscle)
NCC hyperactivation ↑ arterial tone
│ │
▼ ▼
↑ NaCl reabsorption vascular contribution
↓ distal Na+ delivery │
│ │
▼ │
Hyperkalemia + ───► HYPERTENSION ◄┘
metabolic acidosis
Upstream vs downstream: Upstream = CUL3 ligase defect → WNK accumulation. Downstream = SPAK/OSR1 → NCC → NaCl retention → clinical phenotype. Cell types: DCT epithelial cell (CL:1000768 kidney distal convoluted tubule epithelial cell), vascular smooth muscle cell (CL:0000359). GO biological processes: GO:0000209 (protein polyubiquitination), GO:0035725 (sodium ion transmembrane transport), GO:0008217 (regulation of blood pressure).
Biochemical diagnosis. PHA2E is suspected on the triad of hyperkalemia, hyperchloremic metabolic acidosis, and hypertension with suppressed plasma renin and normal GFR, with normal or high aldosterone and hypercalciuria (PMID: 27369102; PMID: 6384650).
| Test | Finding in PHA2E | Notes |
|---|---|---|
| Serum potassium | Elevated (hyperkalemia) | HP:0002153 |
| Serum chloride / bicarbonate | Hyperchloremia, low HCO₃ (metabolic acidosis) | HP:0004879 |
| Plasma renin activity | Suppressed/low | diagnostic clue |
| Plasma aldosterone | Normal or high | distinguishes from hypoaldosteronism |
| Urinary calcium | Elevated (hypercalciuria) | HP:0002150 |
| eGFR | Normal | rules out renal failure |
| Urinary exosomal NCC | Increased NCC abundance | supportive, research/translational (PMID: 28511177) |
Genetic testing (confirmatory). Diagnosis is confirmed by molecular testing of the four FHHt genes — WNK1, WNK4, KLHL3, CUL3 — via next-generation sequencing (gene panel or exome), with attention to splice-site variants causing CUL3 exon-9 skipping. Network-medicine-informed diagnostic panels (e.g., PHA-X incorporating CNV detection and ACMG/AMP curation) have been proposed (PMID: 41569463). Genetic testing is indispensable for precise subtyping, which directs etiology-specific management and prognostication (PMID: 41982973).
Differential diagnosis. PHAII must be distinguished from conditions producing hypotension: PHA type I (salt-wasting, hypotension, elevated aldosterone), type 4 RTA/hypoaldosteronism (aldosterone deficiency, low BP), and other causes of hyperkalemia (renal failure, drugs). The discriminating feature is the direction of blood pressure: "Hyperabsorption of chloride in the distal nephron leads to pseudohypoaldosteronism type II, which is linked with hypertension, whereas blood pressure in the other mentioned disorders is decreased" (PMID: 6384650). A spectacular therapeutic response to thiazide also serves as a diagnostic pointer (PMID: 27369102).
Screening. No newborn or population screening program exists; cascade genetic testing of first-degree relatives is appropriate once a familial variant is identified, though de novo status is common in CUL3.
PHA2E is a chronic, lifelong but highly treatable condition with an excellent prognosis when diagnosed and treated. Thiazide diuretics produce dramatic ("spectacular") normalization of blood pressure and kalemia (PMID: 27369102).
First-line pharmacotherapy — thiazide diuretics. Thiazides directly inhibit the hyperactivated NCC, reversing hypertension, hyperkalemia, and acidosis — often with dramatic effect. Boyden et al.: "Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location" (PMID: 22266938). Glover et al. confirm FHHt "is effectively treated by thiazide diuretics and/or dietary salt restriction" (PMID: 24266877). NCIT: thiazide diuretic (e.g., hydrochlorothiazide, NCIT:C29181); chlorthalidone.
Dietary / supportive measures. Sodium (salt) restriction reduces substrate for NaCl retention; potassium restriction and, if needed, potassium-binding resins address hyperkalemia. Klaus: "sodium restriction and chloruretic diuretics (thiazide) in type II of pseudohypoaldosteronism" (PMID: 6384650).
Treatment strategy / personalized medicine. PHA2E is a model of genotype-guided therapy: identifying a CUL3/KLHL3-WNK pathway defect directs clinicians specifically to NCC-blocking thiazides rather than empirical antihypertensives. The CUL3/KLHL3–WNK–SPAK/OSR1 pathway is itself being pursued as a target for novel antihypertensive agents, with the appeal that "its inhibition may not only reduce renal sodium reabsorption along multiple segments but may also reduce vascular tone" (PMID: 27076645).
Advanced/experimental therapeutics: No gene therapy, cell therapy, or RNA-based therapy is clinically available or in trials specifically for PHA2E; the pathway (WNK/SPAK inhibitors) is at the preclinical/translational stage.
Treatment outcomes and adverse events: Response is typically excellent and rapid. Thiazide adverse effects to monitor include hypokalemia (useful here, as it counters the hyperkalemia), hyponatremia, hyperuricemia, and volume depletion; doses are titrated to normalize potassium and blood pressure.
Primary model — CUL3Δ403-459 knock-in mouse. A knock-in mouse carrying the PHA2E deletion faithfully recapitulates the disease: "Deletion of exon 9 from CUL3 (affecting residues 403-459, CUL3(Δ403-459)) causes a severe form of FHHt (PHA2E) that is recapitulated closely in a knock-in mouse model" (PMID: 27378813).
| Model | Type | Key findings | Reference |
|---|---|---|---|
| CUL3^WT/Δ403-459^ knock-in mouse | Mammalian, knock-in (heterozygous) | Recapitulates hyperkalemia/hypertension; reveals arterial pulse-waveform changes = vascular component | PMID: 26286618 |
| CUL3Δ403-459 mouse (ROMK study) | Mammalian, knock-in | NCC activation via WNK accumulation; ROMK expression unaltered → hyperkalemia from reduced distal Na⁺ delivery | PMID: 27378813 |
| Renal CSN (JAB1)-deficient mouse | Mammalian, conditional (Pax8/LC1) | Deficient COP9-signalosome binding contributes importantly to the FHHt phenotype | PMID: 30301860 |
| DCT-specific CSN disruption mouse | Mammalian, conditional | DCT-specific CSN disruption (not CUL3 itself) causes tubular injury | PMID: 39205661 |
| Cultured kidney cells expressing Cul3Δ403-459 | In vitro | Dissected dual gain/loss of function; JAB1 fails to bind deleted 4-helix bundle | PMID: 29897280 |
Phenotype recapitulation: Excellent — the knock-in mouse reproduces the renal electrolyte/hypertension phenotype and additionally uncovered the vascular contribution not previously appreciated. Limitations: Mouse models of the mutant have been central to resolving the still-debated balance of gain-of-function vs loss-of-function mechanisms (PMID: 29361671); subtle human features (dental abnormalities, growth retardation) are less emphasized in models. Applications: Dissecting the CUL3-CSN-WNK-SPAK-NCC cascade, testing WNK/SPAK inhibitors, and probing renal vs vascular contributions to hypertension.
Boyden et al. (2012) identified CUL3 and KLHL3 as PHAII genes across 41 families; CUL3 mutations are dominant and predominantly de novo, and diverse mutations converge on exon-9 skipping (CUL3Δ403-459). "KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo" and "Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion" (PMID: 22266938).
"In CUL3-∆9-mediated FHHt, proteasomal degradation of WNKs is abrogated, leading to overactivation of the WNK targets [SPAK] and oxidative stress-response kinase-1, which directly phosphorylate and activate the thiazide-sensitive Na[-Cl cotransporter]" (PMID: 29361671); NCC hyperactivation occurs along the DCT, producing hypertension and hyperkalemia (PMID: 39699086).
"Autosomal dominant mutations in cullin-3 (Cul3) cause the most severe form of familial hyperkalemic hypertension (FHHt)" (PMID: 29361671); disease features reverse with thiazides (PMID: 22266938).
"Deletion of exon 9 from CUL3 ... causes a severe form of FHHt (PHA2E) that is recapitulated closely in a knock-in mouse model" (PMID: 27378813).
"the PHA2E mutant, CUL3(Δ403-459), is severely compromised in its ability to ubiquitylate WNKs ... Instead, CUL3(Δ403-459) auto-ubiquitylates and loses interaction with two important Cullin regulators: the COP9-signalosome and CAND1"; "These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases" (PMID: 26286618); dual gain/loss of function and JAB1/CSN disruption (PMID: 29897280; PMID: 30301860).
"These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models" (PMID: 26286618); the WNK-OSR1/SPAK-SLC12a cascade is present in VSMCs and regulates arterial tone (PMID: 26152401).
"The typical clinical picture ... includes ... arterial hypertension and dyskaliemia, hyperchloremia metabolic acidosis, hypercalciuria, a low rate of renin, and most frequently, a normal or high rate of aldosterone. Dental abnormalities and growth retardation can also be associated" (PMID: 27369102); growth/developmental impairment from persistent acidosis/hypertension (PMID: 41380172).
| PMID | Title (abbrev.) | Role |
|---|---|---|
| 22266938 | Mutations in KLHL3 and CUL3 cause hypertension and electrolyte abnormalities | Landmark: identifies CUL3 cause, exon-9 skipping, de novo dominance, thiazide reversal |
| 29361671 | Mechanisms and controversies in mutant Cul3-mediated FHHt | Core mechanism; CUL3 = most severe FHHt |
| 39699086 | Familial Hyperkalemic Hypertension | NCC/DCT localization of lesion |
| 26286618 | Characterisation of the Cullin-3 mutation... | Protein dysfunction; CSN/CAND1 loss; vascular component |
| 29897280 | Dual gain and loss of cullin 3 function... | Mechanistic dissection; JAB1/CSN |
| 30301860 | Renal COP9 Signalosome Deficiency... | CSN binding deficiency drives FHHt |
| 27378813 | ROMK expression unaltered in CUL3Δ403-459 mouse | Knock-in model; hyperkalemia mechanism |
| 26152401 | KLHL3/CUL3 ubiquitin ligase and WNK signaling... | Vascular smooth muscle pathway |
| 27076645 | The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as antihypertensive target | Pathway definition; drug target |
| 27369102 | Gordon syndrome: BP measurement in children | Clinical phenotype; CUL3 pediatric case; thiazide response |
| 41380172 | Diagnostic pitfalls... 9-year follow-up of early-onset PHAII | Morbidity; growth/developmental impairment |
| 24266877 | Detection of mutations in KLHL3 and CUL3 in FHHt families | Epidemiology; treatment |
| 39229746 | Prevalence of Hyperkalemia and FHHt in 5100 patients | Rarity; diagnosis importance |
| 11903313 | Phenotypic/genetic heterogeneity of FHHt | Historical epidemiology; AD inheritance; variable expressivity |
| 6384650 | Primary hypoaldosteronism, pseudo-hypoaldosteronism... | Differential diagnosis; thiazide treatment |
| 41569463 | PHA demystification; diagnostic panels | Diagnostic panel design |
| 41982973 | Chinese children with PHA case series | Value of genetic subtyping |
Report compiled from autonomous iterative investigation (5 iterations, 13 confirmed findings, 30 papers reviewed). Evidence source types span human clinical case reports/series, model-organism (mouse knock-in) studies, and in vitro mechanistic studies, as noted throughout.
Checked with linkml-reference-validator 0.4.0.
| Outcome | Count |
|---|---|
| References checked | 21 |
| Resolved | 21 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 21 |
| On topic | 18 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 23 |
| Resolved | 22 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 21 |
| Terms named correctly | 9 |
| Terms named as a different term | 5 |
| Terms whose name is worth a second look | 7 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0013782 (3 mentions) - the report calls it "MONDO", "PHA2E"; MONDO calls it pseudohypoaldosteronism type 2EHP:0002153 (3 mentions) - the report calls it "Laboratory abnormality", "Elevated (hyperkalemia)", "Hyperkalemia"; HP calls it HyperkalemiaHP:0004879 (3 mentions) - the report calls it "Hyperchloremia, low HCO₃ (metabolic acidosis)"; HP calls it Intermittent hyperventilationHP:0002150 (3 mentions) - the report calls it "Laboratory abnormality", "Elevated (hypercalciuria)", "Hypercalciuria"; HP calls it HypercalciuriaHP:0004322 (1 mention) - the report calls it "Physical manifestation"; HP calls it Short statureThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0001947 (2 mentions) - the report calls it "Hyperchloremic metabolic acidosis"; HP calls it Renal tubular acidosisHP:0000164 (2 mentions) - the report calls it "Abnormality of the teeth", "Dental abnormality"; HP calls it Abnormality of the dentition, and lists "Abnormality of the teeth" among its other namesGO:0000209 (3 mentions) - the report calls it "Cellular processes: Protein polyubiquitination", "protein polyubiquitination"; GO calls it protein polyubiquitination**GO:0031463 (4 mentions) - the report calls it "Cul3-RING ligase complex", "Cul3-RING ubiquitin ligase complex"; GO calls it Cul3-RING ubiquitin ligase complexCL:1000768 (3 mentions) - the report calls it "kidney distal convoluted tubule epithelial cell"; CL calls it kidney connecting tubule epithelial cellUBERON:0002113 (2 mentions) - the report calls it "Primary organ: Kidney", "kidney"; UBERON calls it kidney**, and lists "reniculate kidney" among its other namesUBERON:0001292 (2 mentions) - the report calls it "renal distal convoluted tubule (DCT)", "distal convoluted tubule"; UBERON calls it distal convoluted tubuleThe report gives these identifiers more than one name of its own:
MONDO:0013782 - called "MONDO", "PHA2E"HP:0002153 - called "Laboratory abnormality", "Elevated (hyperkalemia)", "Hyperkalemia"HP:0002150 - called "Laboratory abnormality", "Elevated (hypercalciuria)", "Hypercalciuria"HP:0000164 - called "Abnormality of the teeth", "Dental abnormality"GO:0000209 - called "Cellular processes:** Protein polyubiquitination", "protein polyubiquitination"GO:0031463 - called "Cul3-RING ligase complex", "Cul3-RING ubiquitin ligase complex"UBERON:0002113 - called "Primary organ:** Kidney", "kidney"UBERON:0001292 - called "renal distal convoluted tubule (DCT)", "distal convoluted tubule"