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Inheritance

2

Autosomal dominant inheritance HP:0000006

Heterozygous missense KLHL3 variants clustered in the Kelch propeller and BTB domains segregate with the trait under a dominant model. They are inferred to act as dominant negatives because they phenocopy recessive loss of function, and because mice heterozygous for a KLHL3 null allele are unaffected while a heterozygous R528H knock-in is not. KLHL3 dimerization supplies the mechanism: a mutant subunit disables the heterodimer it joins.

Autosomal dominant inheritance

Show evidence (5 references)

PMID:22266938 SUPPORT Human clinical

"Sixteen kindreds have heterozygous mutations that co-segregate with the trait under a dominant model"

Sixteen KLHL3 kindreds show dominant co-segregation of a heterozygous variant.

PMID:22266938 SUPPORT Human clinical

"Importantly, we infer that mutations in dominant kindreds are likely dominant-negative, because they phenocopy the features of recessive disease."

States the dominant-negative inference for the heterozygous KLHL3 alleles.

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"PHAII is frequently inherited in an autosomal dominant manner; PHAIID (caused by pathogenic variants in KLHL3) may also be inherited in an autosomal recessive manner."

GeneReviews records both modes for the KLHL3 form specifically.

+ 2 more references

Autosomal recessive inheritance HP:0000007

Biallelic KLHL3 variants, homozygous or compound heterozygous, cause the same disease in kindreds where affected members are confined to siblings who inherited both alleles while relatives carrying none or one are unaffected. Recessive alleles are distributed throughout the protein rather than clustered, and consanguinity underlies several of the reported families. Recessive transmission was unknown for pseudohypoaldosteronism type II before KLHL3 was identified, and KLHL3 remains the only familial hyperkalemic hypertension gene with a recessive form.

Autosomal recessive inheritance

Show evidence (5 references)

PMID:22266938 SUPPORT Human clinical

"In these kindreds, affected members are confined to siblings of index cases who inherited the same two mutations, while unaffected relatives inherited zero or one mutation"

Segregation in the eight biallelic KLHL3 kindreds follows a recessive model.

PMID:22266938 SUPPORT Human clinical

"Recessive transmission has not been previously described for PHAII."

Records that the recessive mode was first established through KLHL3.

PMID:28511177 SUPPORT Human clinical

"A family with recessive FHHt caused by a new KLHL3 mutation, S553L, is described."

An independent consanguineous family carrying a recessive KLHL3 allele.

+ 2 more references

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Discussions and Knowledge Gaps

4

What mechanism produces the metabolic acidosis in KLHL3-related pseudohypoaldosteronism type 2, and is it the same mechanism as in the WNK4 form?

KNOWLEDGE GAP acidosis_mechanism_in_klhl3_disease

Attached to

pathophysiology#Hyperkalemia-Driven Impairment of Renal Ammonium Excretion

Two incompatible accounts exist and neither was obtained in a KLHL3 genotype. The constitutively active SPAK mouse, which isolates cotransporter hyperactivation, makes the acidosis secondary to hyperkalemia through proximal tubule ammonia generation and collecting duct ammonia transport, and that is the chain this entry encodes. The WNK4 Q562E mouse instead attributes it to excessive collecting duct bicarbonate secretion through pendrin, with normal proton secretion and ammonium excretion. A cohort of 18 human WNK4 Q565E patients had renal ammonium excretion no lower than unaffected subjects, which fits neither mouse cleanly. Whether the KLHL3 form follows either account is untested.

Proposed experiments

Acid-base and ammonia handling in KLHL3 R528H knock-in and KLHL3 null mice

klhl3_acid_base_ammonia_handling

Measure urinary ammonium excretion, urine pH under an acid load, proximal tubule ammoniagenic enzyme expression and collecting duct Rhcg abundance in Klhl3 R528H/+ and Klhl3 null mice, before and after thiazide correction of the hyperkalemia, and test whether pendrin deletion corrects the acidosis as it does in the WNK4 model.

Readouts

Urinary ammonium excretion

pathophysiology#Hyperkalemia-Driven Impairment of Renal Ammonium Excretion

Direction: DECREASED

Interpretation: The quantity the encoded mechanism predicts will fall, and the one the human WNK4 cohort did not show falling.

Would support

pathophysiology#Hyperkalemia-Driven Impairment of Renal Ammonium Excretion

Supporting outcome

Reduced urinary ammonium excretion with reduced proximal ammoniagenic enzyme expression that normalises when a thiazide corrects the potassium
No correction of the acidosis by pendrin deletion in a KLHL3 genotype

Refuting outcome

Normal ammonium excretion with correction of the acidosis by pendrin deletion, which would place the KLHL3 form with the WNK4 bicarbonate secretion account instead

By what mechanism does hypercalciuria arise in KLHL3-related pseudohypoaldosteronism type 2?

KNOWLEDGE GAP hypercalciuria_mechanism_in_klhl3_disease

Attached to

phenotypes#Hypercalciuria

Hypercalciuria is established as a feature of KLHL3-mutant families and is milder than in the WNK4 Q565E form, but the only mechanistic work is in the WNK4 D561A mouse, where reduced paracellular calcium reabsorption in the thick ascending limb was implicated and TRPV6 and calbindin rose as an apparent compensation. Nothing of the kind has been measured in a KLHL3 genotype, and the milder human phenotype suggests the two may not share a mechanism. The phenotype is therefore left unconnected in the pathograph rather than attached to the cotransporter node by inference.

Proposed experiments

Renal calcium handling in KLHL3 R528H knock-in mice

klhl3_renal_calcium_handling

Measure urinary calcium excretion, the furosemide-induced calciuric response as a probe of thick ascending limb paracellular transport, and TRPV5, TRPV6 and calbindin abundance in Klhl3 R528H/+ mice, for direct comparison with the published WNK4 D561A data.

Would support

phenotypes#Hypercalciuria

Supporting outcome

Raised urinary calcium with a blunted furosemide calciuric response, matching the thick ascending limb account from the WNK4 model

Refuting outcome

Raised urinary calcium with a normal furosemide response, which would place the defect distally and separate the KLHL3 mechanism from the WNK4 one

Does a recessive KLHL3 missense allele behave like a null allele in vivo?

KNOWLEDGE GAP recessive_missense_versus_null

Attached to

pathophysiology#Loss of KLHL3 Substrate Adaptor Function genetic#KLHL3

The recessive human genotypes include missense alleles such as S410L, which destabilises the protein as well as weakening WNK4 binding, and S553L, whose biochemistry has not been characterised. The only in vivo model of the recessive form is a complete gene deletion, which the review literature takes as standing in for the recessive alleles. That substitution is untested, and it matters for the severity ranking: recessive KLHL3 disease is the most severe of the four genes after CUL3, which a pure null would be expected to explain but a partially functional missense allele would not.

Proposed experiments

Knock-in mice carrying recessive human KLHL3 missense alleles

recessive_klhl3_missense_knockins

Generate homozygous Klhl3 S410L and S553L knock-in mice and compare renal WNK1, WNK4, phosphorylated SPAK and phosphorylated NCC abundance, blood pressure and electrolytes against Klhl3 null and wild-type littermates.

Would support

pathophysiology#Loss of KLHL3 Substrate Adaptor Function

Supporting outcome

Homozygous missense knock-ins phenocopy the null for WNK accumulation and electrolytes, which would justify using the null as a model of recessive disease

Refuting outcome

A milder or qualitatively different phenotype in the missense knock-ins, which would mean the published recessive model overstates the genotype it stands for

Would a direct WNK or SPAK/OSR1 inhibitor treat this disease better than a thiazide?

OPEN QUESTION upstream_cascade_inhibitors

Attached to

pathophysiology#SPAK and OSR1 Hyperactivation treatments#Thiazide diuretic therapy

Thiazides work and are the standard of care, but chronic use carries class side effects and provokes compensatory nephron adaptation that offsets the drug. The epistasis experiments make an unusually specific prediction about the alternative: in the WNK4 D561A mouse, removing SPAK alone abolished the phenotype while removing OSR1 in the kidney tubule did not, so a SPAK-selective inhibitor would be expected to work and an OSR1-selective one would not. Molecular inhibitors of the pathway are under development, but none has been tested in a KLHL3 genotype or in patients with this disease.

Proposed experiments

SPAK-selective inhibition in KLHL3 R528H knock-in mice

spak_inhibitor_in_klhl3_knockin

Give a SPAK-selective inhibitor and, in parallel, a thiazide to Klhl3 R528H/+ mice on a normal and a high-salt diet, and compare blood pressure, serum potassium and bicarbonate, phosphorylated NCC abundance, and the compensatory nephron remodelling that chronic thiazide treatment induces.

Would support

pathophysiology#SPAK and OSR1 Hyperactivation

Supporting outcome

Correction of blood pressure, potassium and bicarbonate at least equal to the thiazide arm, with lower phosphorylated NCC and without the compensatory remodelling the thiazide arm shows

Refuting outcome

No improvement in the electrolyte or blood pressure abnormalities, which would mean SPAK inhibition does not reach the cascade in a KLHL3 genotype even though Spak deletion rescues the WNK4 one

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Pathophysiology

13

Dominant-Negative Poisoning of KLHL3 Dimers

Heterozygous KLHL3 missense alleles in the Kelch propeller and BTB domains do not merely halve adaptor dose. KLHL3 dimerizes, so a mutant subunit disables the heterodimer it joins and only wild-type homodimers remain functional. The genetic evidence is an asymmetry in mice: heterozygotes for a KLHL3 null allele are unaffected and accumulate no renal WNK, whereas heterozygous human missense carriers and heterozygous R528H knock-in mice have the full phenotype.

KLHL3 hgnc:6354

Genetic context variant_origin: GERMLINE functional_impact_category: DOMINANT_NEGATIVE

Animal models

KLHL3 knockout mouse Mouse fails to recapitulate The heterozygous null does not develop the disease, so this model does not reproduce the dominant human phenotype. That negative result is the argument for the dominant-negative mechanism rather than a shortcoming of the experiment.

Downstream

Loss of KLHL3 Substrate Adaptor Function Poisoned heterodimers leave the CUL3-KLHL3 complex unable to present its WNK substrates, the same end state as biallelic loss.

Show evidence (2 references)

PMID:28052936 SUPPORT Model organism

"This clearly demonstrates that the heterozygous deletion of KLHL3 was not sufficient to cause PHAII, indicating that autosomal dominant type PHAII is caused by the dominant negative effect of mutant KLHL3."

Heterozygous null mice are unaffected, so the dominant human alleles must act as dominant negatives.

PMID:22266938 SUPPORT Human clinical

"Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates."

The dominant alleles phenocopy recessive loss of function, the original argument for a dominant-negative mechanism.

KLHL3 Serine 433 Phosphorylation Blocking WNK Binding

Phosphorylation of KLHL3 at serine 433, inside the Kelch domain, prevents WNK4 from binding and so prevents its degradation. This is the physiological switch by which angiotensin II, dietary potassium restriction, insulin and vasopressin signalling raise WNK levels, and calcineurin reverses it. The disease alleles S433G and S433N occupy that residue, so PHA2D includes a genetic lock of a normally regulated switch. The same node explains why calcineurin inhibitors produce an acquired phenocopy.

KLHL3 hgnc:6354

KLHL3 serine 433 phosphorylation GO:0006468 ↑ INCREASED

Downstream

Loss of KLHL3 Substrate Adaptor Function Serine 433 phosphorylation, or its genetic mimicry, abolishes substrate binding without changing adaptor abundance.

Show evidence (5 references)

PMID:25313067 SUPPORT Model organism

"AII administration to mice, even in the absence of volume depletion, induces renal KLHL3(S433) phosphorylation and increased levels of both WNK4 and the NaCl cotransporter."

Angiotensin II drives the same serine 433 phosphorylation in vivo with the expected WNK4 and cotransporter response.

PMID:26435498 SUPPORT In vitro / ex vivo

"In conclusion, we found that Akt and PKA phosphorylated KLHL3 at S433, and phosphorylation of KLHL3 by PKA inhibited WNK4 degradation."

Protein kinase A and Akt converge on the same residue, placing insulin and vasopressin signalling on this node.

PMID:27942049 SUPPORT Model organism

"In the distal convoluted tubules of mice eating a low-K+ diet, we found increased KLHL3 phosphorylation at S433 (KLHL3S433-P), a modification that impairs WNK binding, and also reduced total KLHL3 levels."

Dietary potassium restriction uses the same switch in the distal convoluted tubule.

+ 2 more references

Loss of KLHL3 Substrate Adaptor Function

KLHL3 is the BTB-BACK-Kelch substrate adaptor that recruits WNK kinases to a CUL3-based ubiquitin ligase complex. Disease alleles remove that function by three converging routes: abolished WNK binding through the Kelch propeller, abolished CUL3 binding through the BTB domain, and in the S410L case reduced adaptor stability. The protein is expressed where the disease acts, predominantly in the distal convoluted tubule and collecting duct with apical localization in the distal convoluted tubule.

kidney distal convoluted tubule epithelial cell CL:1000849

KLHL3 hgnc:6354

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

KLHL3 ubiquitin ligase substrate adaptor activity GO:1990756 ↓ DECREASED

Animal models

KLHL3 knockout mouse Mouse recapitulates Complete loss of the adaptor produces the disease phenotype, and the review literature reads the homozygous null as the closest available model of the recessive human form.

Downstream

Failed CUL3-KLHL3 Ubiquitination of WNK Kinases Without a functional adaptor the ligase complex cannot ubiquitylate its WNK substrates.

Show evidence (4 references)

PMID:23665031 SUPPORT In vitro / ex vivo

"We conclude that KLHL3 is a substrate adaptor for WNK4 in a ubiquitin E3 ligase complex."

Establishes the adaptor role that disease alleles remove.

PMID:23665031 SUPPORT In vitro / ex vivo

"All five PHAII mutations of KLHL3 tested disrupted the regulation on WNK4."

Every disease allele tested lost the regulatory effect on WNK4.

PMID:22406640 SUPPORT In vitro / ex vivo

"The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes."

Places KLHL3 in the substrate-recruiting family for CUL3 ligases.

+ 1 more reference

Failed CUL3-KLHL3 Ubiquitination of WNK Kinases

The wild-type CUL3-KLHL3 complex polyubiquitylates WNK1 and WNK4, tagging them for proteasomal destruction; at least fifteen ubiquitination sites have been mapped in WNK4. Loss of adaptor function removes that tag.

WNK kinase ubiquitination by the CUL3-KLHL3 complex GO:0016567 ↓ DECREASED

Cul3-RING ubiquitin ligase complex GO:0031463

Downstream

WNK1 and WNK4 Kinase Accumulation Untagged WNK kinase escapes proteasomal degradation, so its steady-state protein level rises.

Show evidence (4 references)

PMID:23576762 SUPPORT In vitro / ex vivo

"We show that this binding leads to ubiquitination, including polyubiquitination, of at least 15 specific sites in WNK4, resulting in reduced WNK4 levels."

Maps the ubiquitination the complex normally performs on WNK4.

PMID:23576762 SUPPORT In vitro / ex vivo

"Dominant disease-causing mutations in KLHL3 and WNK4 both impair WNK4 binding, ubiquitination, and degradation."

Disease alleles in both genes converge on this failed ubiquitination step.

PMID:23387299 SUPPORT In vitro / ex vivo

"Moreover, siRNA (small interfering RNA)-mediated knockdown of CUL3 increased WNK1 protein levels and kinase activity in HeLa cells."

Removing the ligase scaffold raises WNK1 protein and kinase activity, the expected consequence of losing the complex.

+ 1 more reference

WNK1 and WNK4 Kinase Accumulation

Both WNK substrates accumulate in the kidney when the adaptor fails, and the accumulation is kidney-restricted even though KLHL3 is expressed elsewhere. This is the point at which the KLHL3 and CUL3 forms of the disease join the WNK1 and WNK4 forms, where variants in the kinases themselves produce the same excess of WNK activity.

WNK1 hgnc:14540 WNK4 hgnc:14544

proteasomal degradation of WNK kinases GO:0043161 ↓ DECREASED

Animal models

KLHL3 R528H knock-in mouse Mouse recapitulates Both WNK substrates accumulate in the kidney of the heterozygous knock-in, and the mutant protein binds neither.

Downstream

SPAK and OSR1 Hyperactivation Excess WNK kinase phosphorylates and activates its downstream kinases SPAK and OSR1.

WNK4-Mediated Suppression of ROMK and BK Channels Separately from its action on the cotransporter, excess WNK4 acts directly on the secretory potassium channels of the downstream segments, so this branch of the mechanism does not run through NCC.

Show evidence (2 references)

PMID:28052936 SUPPORT Model organism

"the expression levels of WNK kinases were not increased in any of these organs other than the kidney, where WNK1 and WNK4 increased in KLHL3-/- mice but not in KLHL3+/- mice"

WNK accumulation on loss of KLHL3 is confined to the kidney.

PMID:39699086 SUPPORT REVIEW SYNTHESIS Other

"CUL3 and KLHL3 are now known to form a ubiquitin ligase complex that promotes proteasomal degradation of WNK kinases, which activate downstream kinases that phosphorylate and thus activate NCC."

States the whole adaptor-to-cotransporter chain in which this node is the middle step.

SPAK and OSR1 Hyperactivation

The WNK kinases act on the cotransporter through two closely related kinases, SPAK (STK39) and OSR1 (OXSR1), which phosphorylate NCC directly. Genetic epistasis in the WNK4 D561A mouse shows this cascade is not merely correlated with the disease but required for it: deleting Spak abolished the phenotype, kidney-specific Osr1 deletion did not, and knock-ins preventing WNK-mediated activation of both kinases corrected the whole triad. SPAK is therefore the principal effector.

STK39 hgnc:17717 OXSR1 hgnc:8508

SPAK and OSR1 protein serine/threonine kinase activity GO:0004674 ↑ INCREASED

Downstream

NCC Hyperphosphorylation in the Distal Convoluted Tubule SPAK and OSR1 phosphorylate the sodium chloride cotransporter, which activates it and promotes its accumulation at the apical membrane.

Show evidence (3 references)

PMID:29361671 SUPPORT REVIEW SYNTHESIS Other

"proteasomal degradation of WNKs is abrogated, leading to overactivation of the WNK targets sterile 20/SPS-1 related proline/alanine-rich kinase and oxidative stress-response kinase-1, which directly phosphorylate and activate the thiazide-sensitive Na+-Cl- cotransporter"

Names SPAK and OSR1 as the kinases that directly phosphorylate and activate the cotransporter downstream of failed WNK degradation. Written of the CUL3 form, which shares this cascade with the KLHL3 one.

PMID:24039833 SUPPORT Model organism

"Wnk4 (D561A/+).KSP-Osr1 (-/-) remained phenotypically PHA II while Wnk4 (D561A/+).Spak (-/-) mice became normotensive and lacked the PHA II phenotype."

Identifies SPAK rather than OSR1 as the kinase whose loss rescues the phenotype. Shown in the WNK4 D561A mouse, which shares this cascade with the KLHL3 form.

PMID:21486947 SUPPORT Model organism

"the high blood pressure, hyperkalemia and metabolic acidosis observed in Wnk4(D561A/+) mice were corrected in the triple knock-in mice"

The whole clinical triad depends on this cascade being activatable. Again in the WNK4 genotype, cited for the shared cascade rather than for KLHL3.

NCC Hyperphosphorylation in the Distal Convoluted Tubule

Phosphorylated NCC accumulates at the apical membrane of the distal convoluted tubule, raising its sodium chloride transport activity. KLHL3 normally acts on this step from the other side as well, by downregulating the cotransporter at the cell surface. The excess is measurable in patients as raised urinary exosomal NCC abundance.

kidney distal convoluted tubule epithelial cell CL:1000849

SLC12A3 hgnc:10912

NCC sodium:chloride symporter activity GO:0015378 ↑ INCREASED

Animal models

KLHL3 R528H knock-in mouse Mouse recapitulates Renal cotransporter phosphorylation is increased, with the salt-sensitive hypertension, hyperkalemia and acidosis that follow from it.

Downstream

Increased Distal Nephron Sodium Chloride Reabsorption An activated cotransporter at the apical membrane moves more sodium and chloride out of the tubular lumen.

Show evidence (3 references)

PMID:24821705 SUPPORT Model organism

"Moreover, the phosphorylation of NCC was increased in the KLHL3(R528H/+) mouse kidney, indicating that the KLHL3(R528H/+) knock-in mouse is an ideal mouse model of PHAII."

Cotransporter phosphorylation is raised in the kidney of the KLHL3 disease model.

PMID:22406640 SUPPORT In vitro / ex vivo

"KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface."

KLHL3 normally restrains cotransporter surface expression in the same cells.

PMID:28511177 SUPPORT Human clinical

"Increased urinary NCC was found in the affected members of the family with dominant Q309R KLHL3 mutation."

Raised urinary exosomal cotransporter abundance confirms the excess in KLHL3 patients.

Increased Distal Nephron Sodium Chloride Reabsorption

Constitutive sodium chloride reabsorption in the distal convoluted tubule, independent of volume status, is the primary physiological defect of the syndrome. Two consequences follow: the retained salt expands extracellular volume, and sodium that would otherwise travel on to the ENaC-expressing segments is captured upstream. Chloride is retained with it, which the older name chloride shunt syndrome records.

renal sodium ion absorption GO:0070294 ↑ INCREASED

distal convoluted tubule UBERON:0001292

Downstream

Volume Expansion with Renin Suppression Retained sodium chloride expands the extracellular fluid volume.

Reduced Sodium Delivery to ENaC-Expressing Segments Sodium captured in the distal convoluted tubule does not reach the downstream segments where it would drive potassium secretion.

Hyperchloremia The cotransporter carries chloride with sodium, so chloride is retained alongside it.

Show evidence (2 references)

PMID:39699086 SUPPORT REVIEW SYNTHESIS Other

"The primary defect for most forms of FHHt is increased activity of the renal thiazide-sensitive NaCl cotransporter (NCC) expressed along the distal convoluted tubule"

Identifies raised distal cotransporter activity as the primary defect of the syndrome.

PMID:22266938 SUPPORT Human clinical

"constitutively increased salt reabsorption in the distal nephron regardless of volume status"

Describes the volume-independent character of the salt reabsorption this pathway produces.

Volume Expansion with Renin Suppression

Salt retention expands the extracellular volume, which raises blood pressure and suppresses renin release. Suppressed renin is what separates this syndrome from the salt-wasting pseudohypoaldosteronism type 1 disorders, in which renin is high, and the resulting aldosterone level is inappropriately low for the degree of hyperkalemia, which is where the name comes from.

regulation of blood pressure GO:0008217 ↑ INCREASED

Downstream

Hypertension Volume expansion from retained sodium chloride raises arterial pressure.

Suppressed plasma renin Volume expansion suppresses renin release.

Show evidence (2 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels."

Records suppressed renin as part of the syndrome's profile.

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion)."

Explains the inappropriately low aldosterone that gives the syndrome its name.

Reduced Sodium Delivery to ENaC-Expressing Segments

In the late distal convoluted tubule, connecting tubule and cortical collecting duct, ENaC-mediated sodium reabsorption generates the lumen negative voltage that drives potassium secretion through ROMK. When upstream NCC captures the sodium, less of it reaches these segments and that driving force is lost. This node carries the driving-force half of the potassium defect only; the suppression of the channels themselves is a separate branch out of WNK accumulation and has its own node.

kidney collecting duct principal cell CL:1001431

renal sodium ion transport in ENaC-expressing segments GO:0003096 ↓ DECREASED

Downstream

Impaired Distal Potassium Secretion Without ENaC-driven sodium entry there is no electrical driving force for luminal potassium secretion.

Show evidence (1 reference)

PMID:39699086 SUPPORT REVIEW SYNTHESIS Other

"increased NCC activity and the subsequent increase in Na+ reabsorption lowers the delivery to the downstream segments that require Na+ entry through ENaC to drive K+ secretion"

States the reduced sodium delivery to these segments that is this node's own claim.

WNK4-Mediated Suppression of ROMK and BK Channels

Accumulated WNK4 lowers the secretory potassium channels of the distal segments directly, independently of anything happening to NCC. It clears the renal outer medullary potassium channel ROMK from the cell surface, an effect wild-type but not mutant KLHL3 restrains, and it reduces the large-conductance calcium-activated BK channel by promoting its degradation. So the segment loses the channels that would carry potassium out as well as the electrical driving force to push it.

kidney collecting duct principal cell CL:1001431 kidney collecting duct intercalated cell CL:1001432

WNK4 hgnc:14544 KCNJ1 hgnc:6255 KCNMA1 hgnc:6284

ROMK and BK potassium channel activity GO:0005267 ↓ DECREASED

Downstream

Impaired Distal Potassium Secretion Fewer ROMK and BK channels at the apical membrane means less potassium can be secreted for any given driving force.

Show evidence (4 references)

PMID:23576762 SUPPORT In vitro / ex vivo

"WNK4 normally induces clearance of the renal outer medullary K+ channel (ROMK) from the cell surface."

Establishes the WNK4 effect on ROMK that this node asserts.

PMID:23576762 SUPPORT In vitro / ex vivo

"We show that WT but not mutant KLHL3 inhibits WNK4-induced reduction of ROMK level."

Mutant KLHL3 fails to restrain that effect, which is what ties this node to the disease rather than to normal physiology.

PMID:23885063 SUPPORT In vitro / ex vivo

"Our results suggest that WNK4 inhibits BK channel activity, in part, by increasing channel degradation through an ubiquitin-dependent pathway."

Excess WNK4 also lowers the BK channel, the other secretory potassium route of these segments.

+ 1 more reference

Impaired Distal Potassium Secretion

Renal potassium excretion falls despite a normal glomerular filtration rate and a potassium load that would normally drive secretion, producing the hyperkalemia that defines the syndrome.

renal potassium excretion GO:0036359 ↓ DECREASED

Downstream

Hyperkalemia Potassium that cannot be secreted into the tubular lumen accumulates in the extracellular fluid.

Hyperkalemia-Driven Impairment of Renal Ammonium Excretion The hyperkalemia that follows from the secretory defect is in turn what disturbs renal ammonia handling, in the account this entry encodes.

Show evidence (2 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension."

Records that the hyperkalemia occurs with a preserved filtration rate, so it is a secretory defect.

PMID:25313067 SUPPORT BACKGROUND Human clinical

"components of an E3 ubiquitin ligase complex that targets WNKs for degradation--cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia"

Frames impaired potassium secretion as the shared human consequence of mutations in the complex; quoted from this paper's introduction rather than from its own cell and mouse experiments.

Hyperkalemia-Driven Impairment of Renal Ammonium Excretion

The metabolic acidosis of this syndrome is best explained as a secondary consequence of the hyperkalemia rather than as a primary proton secretion defect. In the constitutively active SPAK mouse, which isolates cotransporter hyperactivation from any other effect of the disease genes, correcting the hyperkalemia with a thiazide or with dietary potassium restriction also corrected the acidosis, and the mice showed reduced ammonia-generating enzymes in the proximal tubule with reduced collecting duct ammonia transport.

renal ammonium homeostasis GO:0097272 ↓ DECREASED

Downstream

Hyperchloremic metabolic acidosis Reduced renal ammonium excretion lowers net acid excretion, producing the hyperchloremic acidosis.

Show evidence (1 reference)

PMID:39699086 SUPPORT REVIEW SYNTHESIS Other

"Hydrochlorothiazide administration and dietary K+ restriction, both of which corrected hyperkalemia, also corrected metabolic acidosis in CA-SPAK mice."

Correcting the hyperkalemia corrects the acidosis in the model that isolates cotransporter hyperactivation.

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Pathograph

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Phenotypes

14

Cardiovascular 1

Hypertension FREQUENT HP:0000822

Show evidence (2 references)

ORPHA:757 SUPPORT Other

"HP:0000822 | Hypertension | Very frequent (99-80%)"

Orphanet records hypertension as very frequent in pseudohypoaldosteronism type 2.

PMID:42057493 SUPPORT Human clinical

"This case underscores that normotension in PHA2D may delay diagnosis and that standard thiazide dosing may precipitate hypotension in previously normotensive patients, necessitating highly individualized treatment strategies."

Documents that hypertension can be absent in PHA2D.

Digestive 1

Nausea and vomiting FREQUENT HP:0002017

Show evidence (1 reference)

ORPHA:757 SUPPORT Other

"HP:0002017 | Nausea and vomiting | Frequent (79-30%)"

Orphanet records nausea and vomiting as frequent in pseudohypoaldosteronism type 2.

Endocrine 2

Suppressed plasma renin Decreased circulating renin concentration HP:0003351

Show evidence (2 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"With hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels; AND/OR"

Suppressed plasma renin is one of the GeneReviews clinical diagnostic criteria.

PMID:42057493 SUPPORT Human clinical

"Although this trial improved biochemical markers, it was discontinued once suppressed renin and aldosterone levels pointed toward PHA2."

Suppressed renin and aldosterone redirected the diagnosis in this PHA2D patient.

Aldosterone inappropriately low for the degree of hyperkalemia Abnormal circulating aldosterone concentration HP:0040085

Show evidence (3 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion)."

The GeneReviews statement of the paradox, and the wording this row's name follows.

ORPHA:757 SUPPORT Other

"normal or elevated aldosterone, low renin"

Orphanet's wording, which differs from GeneReviews on the absolute direction and is the reason the umbrella term is bound.

PMID:42057493 SUPPORT Human clinical

"it was discontinued once suppressed renin and aldosterone levels pointed toward PHA2"

In this PHA2D patient aldosterone was frankly suppressed, not merely relatively low.

Genitourinary 1

Hypercalciuria HP:0002150

Show evidence (2 references)

PMID:25925082 SUPPORT Human clinical

"FHHt caused by KLHL3 mutations is accompanied by hypercalciuria as well as hyperkalemia and hypertension."

Establishes hypercalciuria specifically in KLHL3-mutant familial hyperkalemic hypertension.

PMID:25925082 SUPPORT Human clinical

"UCa levels in affected subjects in the two families were significantly higher than in unaffected subjects (0.608 ± 0.196 vs. 0.236 ± 0.053 mmol Ca per mmol creatinine, respectively (p < 0.0001))."

Quantifies the urinary calcium excretion difference in two KLHL3 families.

Head and Neck 1

Abnormal dental enamel morphology OCCASIONAL HP:0000682

Show evidence (1 reference)

ORPHA:757 SUPPORT Other

"HP:0000682 | Abnormality of dental enamel | Occasional (29-5%)"

Orphanet records a dental enamel abnormality as occasional in pseudohypoaldosteronism type 2.

Metabolism 3

Hyperkalemia VERY_FREQUENT HP:0002153

Show evidence (3 references)

ORPHA:757 SUPPORT Other

"HP:0002153 | Hyperkalemia | Very frequent (99-80%)"

Orphanet records hyperkalemia as very frequent in pseudohypoaldosteronism type 2.

PMID:22266938 SUPPORT Human clinical

"| KLHL3 Dominant | 16 | 40 | 24 ±18 | 6.2 ±0.6 | 17.2 ±2.5 | 17 |"

Genotype-stratified mean serum potassium of 6.2 mmol/L in the dominant KLHL3 kindreds.

PMID:42057493 SUPPORT Human clinical

"Laboratory evaluation revealed severe hyperkalaemia and hyperchloremic metabolic acidosis with a normal glomerular filtration rate and persistent normotension."

Severe hyperkalemia with a normal filtration rate in a patient with biallelic KLHL3 disease.

Hyperchloremic metabolic acidosis VERY_FREQUENT HP:0004918

Show evidence (3 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels."

GeneReviews records hyperchloremia with metabolic acidosis as part of the syndrome.

PMID:22266938 SUPPORT Human clinical

"hypertension and acidosis were present in 71% and 82%, respectively"

Acidosis was present in 82 percent of the referral cohort from which the KLHL3 kindreds were drawn.

PMID:42057493 SUPPORT Human clinical

"This overactivity promotes excessive sodium and chloride reabsorption, resulting in hyperkalaemia, hyperchloremic metabolic acidosis, and suppressed renin/aldosterone levels, despite preserved renal function."

Names hyperchloremic metabolic acidosis as a core feature of PHA2D.

Hyperchloremia HP:0011423

Show evidence (2 references)

ORPHA:757 SUPPORT Other

"A rare genetic form of hypertension characterized by hyperkalemia, mild hyperchloremic metabolic acidosis, normal or elevated aldosterone, low renin, with normal renal glomerular filtration rate (GFR)."

Orphanet's definition names hyperchloremic acidosis in the syndrome.

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels."

GeneReviews lists hyperchloremia among the associated findings.

Musculoskeletal 1

Muscle weakness OCCASIONAL HP:0001324

Show evidence (2 references)

ORPHA:757 SUPPORT Other

"HP:0001324 | Muscle weakness | Occasional (29-5%)"

Orphanet records muscle weakness as occasional in pseudohypoaldosteronism type 2.

PMID:42057493 SUPPORT Human clinical

"We report the case of a nine-year-old boy presenting with chronic fatigue, muscle aches, and growth failure."

Muscle symptoms were a presenting complaint in a patient with PHA2D.

Nervous System 1

Periodic paralysis OCCASIONAL HP:0003768

Show evidence (1 reference)

ORPHA:757 SUPPORT Other

"HP:0003768 | Periodic paralysis | Occasional (29-5%)"

Orphanet records periodic paralysis as occasional in pseudohypoaldosteronism type 2.

Constitutional 1

Fatigue HP:0012378

Show evidence (1 reference)

PMID:42057493 SUPPORT Human clinical

"We report the case of a nine-year-old boy presenting with chronic fatigue, muscle aches, and growth failure."

Chronic fatigue was the leading presenting symptom in a patient with PHA2D.

Growth 2

Short stature OCCASIONAL HP:0004322

Show evidence (2 references)

ORPHA:757 SUPPORT Other

"HP:0004322 | Short stature | Occasional (29-5%)"

Orphanet records short stature as occasional in pseudohypoaldosteronism type 2.

PMID:25925082 SUPPORT Human clinical

"Presenting features were short stature in the first family, and transient tachypnea of the newborn (TTN) in the second."

Short stature was the presenting feature in a KLHL3-mutant family.

Growth delay OCCASIONAL HP:0001510

Show evidence (2 references)

ORPHA:757 SUPPORT Other

"HP:0001510 | Growth delay | Occasional (29-5%)"

Orphanet records growth delay as occasional in pseudohypoaldosteronism type 2.

PMID:42057493 SUPPORT Human clinical

"We report the case of a nine-year-old boy presenting with chronic fatigue, muscle aches, and growth failure."

Growth failure was a presenting feature in a patient with PHA2D.

🧬

Genetic Associations

1

KLHL3 (Causative, autosomal dominant (dominant negative) or autosomal recessive (biallelic loss of function))

Gene: KLHL3 hgnc:6354 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (5 references)

PMID:22266938 SUPPORT Human clinical

"Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families."

Identification of KLHL3 as a pseudohypoaldosteronism type II gene.

PMID:22266938 SUPPORT Human clinical

"While recessive KLHL3 mutations are distributed throughout the encoded protein, dominant KLHL3 mutations show striking clustering"

Contrasts the distribution of recessive and dominant KLHL3 alleles.

PMID:22406640 SUPPORT Human clinical

"Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt."

Independent identification of KLHL3 as a familial hyperkalemic hypertension gene.

+ 2 more references

Variants (6)

R528H

Recurrent heterozygous Kelch-domain missense allele, the one modelled in knock-in mice. Mutant KLHL3 R528H binds neither WNK1 nor WNK4, and a CUL3-KLHL3 R528H complex fails to ubiquitylate WNK1 in vitro. Reported in dominant kindreds.

Show evidence (2 references)

PMID:24821705 SUPPORT In vitro / ex vivo

"we measured the binding of TAMRA-labeled WNK1 and WNK4 peptides to full-length KLHL3 using fluorescence correlation spectroscopy, and found that neither WNK1 nor WNK4 bound to mutant KLHL3 R528H"

R528H abolishes binding of both WNK substrates.

PMID:23387299 SUPPORT In vitro / ex vivo

"The recombinant wild-type CUL3-KLHL3 E3 ligase complex, but not a disease-causing CUL3-KLHL3 ... mutant complex, ubiquitylated WNK1 in vitro."

The R528H complex loses WNK1 ubiquitylation activity.

S410L

Kelch-domain allele reported as one half of a compound heterozygous recessive genotype with F322C. It is distinctive in lowering KLHL3 protein stability as well as WNK4 binding affinity.

Show evidence (2 references)

PMID:22266938 SUPPORT Human clinical

"one in which affected members are compound heterozygotes for two missense mutations (F322C and S410L)"

S410L occurs as one allele of a compound heterozygous recessive genotype.

PMID:39699086 SUPPORT REVIEW SYNTHESIS Other

"This indicated that the mechanism for the increase in WNK abundance was reduced stability of the KLHL3 S410L mutant protein."

S410L raises WNK abundance by destabilising the adaptor, not only by losing binding.

W470X

single nucleotide variant

Homozygous nonsense allele in the kindred that first established recessive transmission of pseudohypoaldosteronism type II.

Show evidence (1 reference)

PMID:22266938 SUPPORT Human clinical

"These include one kindred in which affected members are homozygous for a nonsense mutation (W470X)"

A homozygous nonsense KLHL3 allele in a recessive kindred.

S433G and S433N

Kelch-domain alleles substituting serine 433, the residue whose phosphorylation by protein kinase C, protein kinase A or Akt normally prevents WNK binding. A molecular dynamics study shows the phosphate makes the acidic-motif binding pocket more electronegative and dismantles the hydrogen bond network holding WNK4 there, which is why these alleles are read as mimicking the phosphorylated adaptor rather than simply disabling it.

Show evidence (3 references)

PMID:39699086 SUPPORT REVIEW SYNTHESIS Other

"FHHt-causing mutations S433G and S443N likely recapitulate the effect of bona fide phosphorylation of S433 or the phosphomimetic S433E mutation exerting significant structural changes that prevent WNK4 binding to the CUL3-KLHL3 CRL."

Reads the serine 433 substitutions as phosphomimetic. The quoted sentence carries the review's own typographical slip in the second allele name; the correct allele is S433N, as the preceding sentence of that paragraph gives it.

PMID:27727489 SUPPORT Computational

"In conclusion, phosphorylation of KLHL3 at S433 disrupts the hydrogen bonds, hydrophobic and electrostatic interactions between the Kelch domain of KLHL3 and the AM of WNK4."

Supplies the structural account of why a modification or substitution at serine 433 abolishes WNK4 binding.

PMID:27727489 SUPPORT Computational

"phosphorylation of KLHL3 at serine 433, which is also a site frequently mutated in patients"

Confirms that serine 433 is both the regulatory site and a recurrent patient mutation site.

S553L

Homozygous allele in a consanguineous Jewish family of Yemenite origin, one of the few reported recessive KLHL3 genotypes outside the original series. Its biochemistry has not been characterised.

Show evidence (1 reference)

PMID:28511177 SUPPORT Human clinical

"This consanguineous Jewish family of Yemenite extraction, included 2 homozygous and 7 heterozygous affected subjects."

Records the homozygous S553L genotype and the family it was found in.

Q309R

Recurrent heterozygous Kelch-domain allele reported in dominant kindreds, including the family in which raised urinary exosomal NCC abundance was first shown, and one of the two families in which hypercalciuria was quantified.

Show evidence (2 references)

PMID:25925082 SUPPORT Human clinical

"Two new families with FHHt including a total number of 23 subjects, 10 of them affected, in whom previously described mutations in KLHL3 (Q309R and R528H) were identified."

Q309R and R528H were the alleles in the two families studied for hypercalciuria.

PMID:28511177 SUPPORT Human clinical

"Increased urinary NCC was found in the affected members of the family with dominant Q309R KLHL3 mutation."

Q309R carriers showed the raised urinary cotransporter abundance the mechanism predicts.

💊

Medical Actions

4

Thiazide diuretic therapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: hydrochlorothiazide CHEBI:5778

Platform: Small molecule

Thiazides inhibit NCC, the transporter the disease makes overactive, so this is mechanism-directed therapy rather than symptomatic treatment, and it corrects the hyperkalemia, the acidosis and the hypertension together. Dosing needs individual titration: a normotensive child given 0.5 mg/kg/day of hydrochlorothiazide developed symptomatic hypotension and was stabilised on 0.25 mg/kg on alternate days. Chronic use carries class side effects and provokes compensatory adaptation in the nephron, which is what motivates work on direct inhibitors of the cascade upstream.

Mechanism Target:

NCC Hyperphosphorylation in the Distal Convoluted Tubule — Thiazides block the sodium chloride cotransporter that the WNK, SPAK and OSR1 cascade has activated, acting on the proximate cause of the salt retention.

Show evidence (1 reference)

PMID:22266938 SUPPORT Human clinical

"virtually all patients with KLHL3 and CUL3 mutations have been treated with thiazide diuretics, inhibitors of the Na-Cl cotransporter NCC, with correction of phenotypic abnormalities"

Names the cotransporter as the thiazide target and reports correction of the phenotype in KLHL3 patients.

Show evidence (4 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Electrolyte and blood pressure abnormalities of PHAII in children and adults are often corrected with thiazide diuretics."

GeneReviews states the first-line treatment and what it corrects.

PMID:42057493 SUPPORT Human clinical

"The dosage was ultimately titrated to an alternate-day, low-dose regimen (0.25 mg/kg), which successfully maintained metabolic stability while minimizing adverse effects."

Records the reduced, alternate-day regimen needed in a normotensive PHA2D patient.

PMID:41982973 SUPPORT Human clinical

"Management was tailored to the subtype, including aggressive salt supplementation for systemic PHAI and thiazide diuretics for PHAII."

Thiazide diuretics were the treatment used for the KLHL3 and CUL3 patients in this series.

+ 1 more reference

Dietary sodium and potassium restriction

Category: Therapeutic Action: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Because the disease is salt dependent, restricting dietary salt treats the hypertension and restricting potassium treats the hyperkalemia. GeneReviews frames the converse as a circumstance to avoid: untreated patients should not take excessive salt or potassium.

Mechanism Target:

Increased Distal Nephron Sodium Chloride Reabsorption — Reducing the sodium chloride load limits what the overactive cotransporter can retain.

Show evidence (2 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Untreated individuals with PHAII should avoid excessive intake of foods high in salt and potassium as these may exacerbate hypertension and hyperkalemia."

GeneReviews names salt and potassium excess as circumstances to avoid.

PMID:24266877 SUPPORT BACKGROUND Other

"is a salt-dependent form of hypertension caused by mutations in the regulators of the thiazide-sensitive Na+-Cl- co-transporter NCC ... and is effectively treated by thiazide diuretics and/or dietary salt restriction"

States that dietary salt restriction is effective treatment; quoted from this paper's framing of the disease rather than from its own genetic results.

Blood pressure and electrolyte surveillance

Category: Monitoring Action: Supportive Care NCIT:C15747

Routine electrolyte and blood pressure measurement, with blood pressure control pursued for its own sake because of the cardiovascular, renal and cerebrovascular risk the hypertension carries. Pregnancy needs separate handling, since thiazides have been associated with adverse fetal outcome, particularly in the first trimester.

Show evidence (2 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Control of blood pressure is important to reduce the risk of cardiovascular and renal disease and stroke."

GeneReviews states the rationale for blood pressure control beyond electrolyte correction.

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Some antihypertensive medications, including thiazide diuretics, have been associated with adverse fetal outcome, especially when taken during the first trimester of pregnancy; referral to an obstetrics group with expertise in high-risk pregnancies should be considered."

Records the pregnancy caveat on the first-line drug.

Testing of at-risk relatives

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Serum potassium and blood pressure measurement, or targeted testing for the familial variant, identifies affected relatives before complications develop. Zygosity governs who is at risk: in a recessive kindred heterozygous relatives are unaffected, while in a dominant kindred they are not.

Show evidence (2 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Measurement of serum potassium concentration and blood pressure or identification of the known familial CUL3, KLHL3, WNK1, and WNK4 pathogenic variant(s) in first-degree relatives of individuals with PHAII allows for early diagnosis and treatment"

GeneReviews states the evaluation of relatives at risk.

PMID:22266938 SUPPORT Human clinical

"In these kindreds, affected members are confined to siblings of index cases who inherited the same two mutations, while unaffected relatives inherited zero or one mutation"

In recessive kindreds only biallelic relatives are affected, which determines who needs follow-up.

🔬

Diagnosis

3

Biochemical and hormonal profile

Hyperkalemia with a normal glomerular filtration rate, hyperchloremia, metabolic acidosis and suppressed plasma renin, with an aldosterone that is low relative to the potassium level, establishes the clinical diagnosis. Hypertension supports it but is not required.

potassium, serum or plasma LOINC:2823-3 chloride, serum or plasma LOINC:2075-0 bicarbonate, serum or plasma LOINC:1963-8

Show evidence (2 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"With hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels; AND/OR"

The GeneReviews clinical diagnostic criteria for pseudohypoaldosteronism type II.

PMID:42057493 SUPPORT Human clinical

"Although this trial improved biochemical markers, it was discontinued once suppressed renin and aldosterone levels pointed toward PHA2."

The hormonal profile redirected this case from mineralocorticoid deficiency to pseudohypoaldosteronism type 2.

Molecular genetic testing of the familial hyperkalemic hypertension genes

Sequencing of KLHL3, CUL3, WNK1 and WNK4 assigns the subtype. KLHL3 is the only one of the four in which a biallelic result is diagnostic as well as a heterozygous one, so zygosity has to be reported and interpreted rather than the variant alone.

Genetic testing NCIT:C15709

Show evidence (2 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"By the identification of a heterozygous pathogenic variant in CUL3, WNK1, or WNK4 or a heterozygous pathogenic variant or biallelic pathogenic variants in KLHL3."

States the molecular diagnostic criterion, and that KLHL3 admits both zygosities.

PMID:41982973 SUPPORT Human clinical

"three with PHAII (heterozygous KLHL3 or CUL3 mutations) exhibiting hyperkalemia and acidosis that were responsive to thiazides"

Genetic testing assigned the subtype in a mixed pseudohypoaldosteronism series including KLHL3 patients.

Urinary exosomal NCC abundance

A research measurement rather than a clinical test. Urinary exosomal NCC is raised in affected KLHL3 carriers, which demonstrates the mechanism in patients rather than only in models. Heterozygous relatives in a recessive family also showed a rise without a clinical phenotype, so the measurement does not separate carriers from patients.

Show evidence (2 references)

PMID:28511177 SUPPORT Human clinical

"Increased urinary NCC was found in affected members (heterozygous) with dominant KLHL3 Q309R, and in affected members (homozygous) of the recessive form."

Urinary cotransporter abundance is raised in affected carriers of both dominant and recessive KLHL3 genotypes.

PMID:28511177 SUPPORT Human clinical

"Unexpectedly, in the recessive disease, heterozygotes seemed to have increased urinary NCC as well, apparently not sufficient quantitatively to produce a clinical phenotype."

Unaffected heterozygotes also showed raised urinary cotransporter abundance, limiting the measurement's diagnostic value.

📈

Progression

2

Biochemical disease without hypertension

Age: Childhood to early adulthood

Hyperkalemia with hyperchloremic metabolic acidosis and suppressed renin typically precedes hypertension in the KLHL3 form. Only 14 percent of recessive and 17 percent of dominant KLHL3 patients were diagnosed with hypertension by age 18, against 94 percent for CUL3, and mean age at diagnosis or referral was in the mid twenties for both KLHL3 classes. A normotensive nine-year-old with biallelic KLHL3 disease has been reported in whom the absence of hypertension delayed diagnosis.

Show evidence (3 references)

PMID:22266938 SUPPORT Human clinical

"| KLHL3 Recessive | 8 | 14 | 26 ±14 | 6.8 ±0.5 | 17.6 ±1.5 | 14 |"

Genotype-stratified row giving a mean diagnosis age of 26 years and 14 percent hypertensive by age 18 for recessive KLHL3.

PMID:22266938 SUPPORT Human clinical

"Subjects with CUL3 mutations presented at much younger ages than those with mutation in KLHL3, WNK1, or WNK4, and had significantly more severe hyperkalemia and metabolic acidosis and were far more likely to have hypertension before age 18 (others commonly develop hypertension at later ages)"

Hypertension in the KLHL3 form commonly appears later than in CUL3 disease.

PMID:42057493 SUPPORT Human clinical

"Laboratory evaluation revealed severe hyperkalaemia and hyperchloremic metabolic acidosis with a normal glomerular filtration rate and persistent normotension."

Documents the biochemical phase without hypertension in a child with PHA2D.

Hypertension and its complications

Age: Adulthood

Hypertension develops in most affected adults and carries the usual cardiovascular, renal and cerebrovascular risk, which is why blood pressure control is part of management rather than electrolyte correction alone.

Show evidence (2 references)

PMID:22073419 SUPPORT REVIEW SYNTHESIS Other

"Control of blood pressure is important to reduce the risk of cardiovascular and renal disease and stroke."

GeneReviews states the rationale for treating the hypertensive phase.

ORPHA:757 SUPPORT Other

"Age of onset: All ages"

Orphanet records onset across all ages for pseudohypoaldosteronism type 2.

📊

Prevalence

1

Worldwide

Point prevalence Not yet documented

Orphanet records the point prevalence of pseudohypoaldosteronism type 2 as unknown across all four causative genes, and no KLHL3-specific figure exists. The published series give the scale rather than a rate: KLHL3 variants were found in 24 index cases of a 52-kindred referral cohort, which is a referral denominator and not a population one.

Show evidence (2 references)

ORPHA:757 SUPPORT Other

"Unknown | Worldwide | Point prevalence | PMID:22073419"

Orphanet epidemiology row recording an unknown worldwide point prevalence.

PMID:22266938 SUPPORT Human clinical

"KLHL3 was sequenced in all PHAII index cases, identifying novel mutations in 24"

Twenty-four of the 52 referred pseudohypoaldosteronism type II kindreds carried a KLHL3 variant.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Pseudohypoaldosteronism Type 2D:

Pseudohypoaldosteronism type 2E MONDO:0013782

Overlapping Features The CUL3 form, biochemically identical but the most severe of the four. It presents far earlier, with deeper hyperkalemia and acidosis, and its variants are dominant and largely de novo rather than inherited.

Distinguishing Features

Much younger age at presentation, and 94 percent hypertensive by age 18 against 17 percent for dominant KLHL3
Dominant and predominantly de novo CUL3 variants, so often no family history
No recessive form, where KLHL3 has one

Show evidence (3 references)

PMID:22266938 SUPPORT Human clinical

"KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo."

Contrasts the inheritance of the KLHL3 and CUL3 forms.

PMID:22266938 SUPPORT Human clinical

"| CUL3 | 17 | 21 | 9 ±6 | 7.5 ±0.9 | 15.5 ±2.0 | 94 |"

The CUL3 row of the genotype-stratified table, with a mean diagnosis age of 9 years and 94 percent hypertensive by age 18.

PMID:41380172 SUPPORT Human clinical

"Pathogenic variants in WNK1, WNK4, KLHL3, and CUL3 have been identified, with CUL3 mutations particularly associated with early-onset and severe phenotypes."

Confirms the early-onset, severe character of the CUL3 form relative to the others.

Pseudohypoaldosteronism type 2B

Overlapping Features The WNK4 form. It shares the mechanism from the WNK accumulation step onwards, since its missense alleles block the same KLHL3 interaction from the substrate side, but it is milder than the KLHL3 form and has only a dominant mode. Its hypercalciuria is more marked.

Distinguishing Features

Milder hyperkalemia and acidosis than the KLHL3 form
Dominant inheritance only
More severe hypercalciuria than in KLHL3 disease

Show evidence (3 references)

PMID:22266938 SUPPORT Human clinical

"Among the other mutant loci, there remain significant differences in disease severity (rank order recessive KLHL3 > dominant KLHL3 > WNK4 > WNK1)."

Places the WNK4 form below both KLHL3 forms in severity.

PMID:25925082 SUPPORT Human clinical

"Hypercalciuria in FHHt with KLHL3 mutations is less severe than that observed in FHHt with the Q565E WNK4 mutation"

Quantifies the difference in hypercalciuria between the KLHL3 and WNK4 forms.

PMID:37285722 SUPPORT In vitro / ex vivo

"This may be one of the reasons why PHAII is less severe when WNK4 is mutated compared to KLHL3 is mutated."

Offers a molecular reason, a second KLHL3-binding motif in WNK4, for the milder WNK4 phenotype.

Pseudohypoaldosteronism type 2A

Overlapping Features The WNK1 form, the mildest of the four, with the latest mean age at diagnosis and the least deranged potassium and bicarbonate.

Distinguishing Features

Mildest biochemistry of the four genes and the latest presentation
Attributed to raised kidney-specific WNK1 rather than a coding change in an adaptor

Show evidence (2 references)

PMID:22266938 SUPPORT Human clinical

"| WNK1 | 2 | 23 | 36 ±20 | 5.8 ±0.8 | 22.4 ±4.6 | 13 |"

The WNK1 row of the genotype-stratified table, with a mean potassium of 5.8 and bicarbonate of 22.4 mmol/L.

PMID:35894282 SUPPORT REVIEW SYNTHESIS Other

"The high sensitivity of KS-WNK1 to KLHL3-targeted degradation and the low levels of L-WNK1 in the DCT, led to propose that this type of FHHt is mainly due to increased KS-WNK1 protein in the DCT."

The WNK1 form is attributed to raised kidney-specific WNK1, the isoform most sensitive to KLHL3-directed degradation.

Calcineurin inhibitor nephrotoxicity

Overlapping Features Tacrolimus and ciclosporin produce an acquired phenocopy. Calcineurin is the phosphatase that removes the KLHL3 serine 433 phosphate, so inhibiting it locks the adaptor in its non-binding state and reproduces the whole cascade. Hypertension and hyperkalemia are common adverse effects of these drugs for this reason.

Distinguishing Features

Temporal relation to starting a calcineurin inhibitor, and no family history
Reversible on withdrawal or dose reduction, where the genetic disease is not

Show evidence (2 references)

PMID:30718414 SUPPORT Model organism

"The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)-CUL3 ubiquitin ligase complex."

States that calcineurin inhibitors mimic the genetic disease, which this paper then traces to the shared serine 433 node.

PMID:30718414 SUPPORT Model organism

"Moreover, tacrolimus attenuates KLHL3-mediated WNK4 ubiquitylation and degradation, while this effect is absent in KLHL3 with S433A substitution."

The drug effect requires serine 433, the residue the S433G and S433N disease alleles occupy.

Hyperkalemic renal tubular acidosis from aldosterone deficiency or resistance

Overlapping Features Hyperkalemic distal renal tubular acidosis from true hypoaldosteronism or from mineralocorticoid resistance gives a similar potassium and acid-base picture. Renin and aldosterone separate them: both are raised in the salt-wasting pseudohypoaldosteronism type 1 disorders and in aldosterone deficiency, and both are suppressed here. A response to fludrocortisone can mislead, since it improved the biochemistry of a PHA2D patient being treated for presumed mineralocorticoid deficiency.

Distinguishing Features

Suppressed renin and aldosterone, where salt-wasting and aldosterone-deficient states have both raised
Volume expansion with hypertension, rather than salt wasting with hypovolemia and hyponatremia
Sustained correction by a thiazide, which addresses the overactive cotransporter

Show evidence (3 references)

PMID:42057493 SUPPORT Human clinical

"Due to an initial clinical suspicion of isolated mineralocorticoid deficiency, a diagnostic trial of fludrocortisone was initiated while awaiting definitive results."

Mineralocorticoid deficiency was the initial working diagnosis in a patient with PHA2D.

PMID:41982973 SUPPORT Human clinical

"Pseudohypoaldosteronism (PHA) is a rare disorder characterized by renal resistance to mineralocorticoids, leading to hyperkalemia, hyponatremia, and metabolic acidosis."

The pseudohypoaldosteronism type 1 disorders share the hyperkalemia and acidosis but add the hyponatremia of salt wasting.

PMID:41380172 SUPPORT Human clinical

"Aldosterone pathway defects may be misdiagnosed during the initial clinical assessment."

Records that aldosterone pathway defects and pseudohypoaldosteronism type 2 are confused on first assessment.

Gordon syndrome (distal arthrogryposis type 3)

Overlapping Features A name collision rather than a clinical differential. The eponym Gordon syndrome is used both for this renal syndrome and for distal arthrogryposis type 3, a musculoskeletal disorder with joint contractures and cleft palate that is curated separately in this knowledge base as `kb/disorders/Gordon_Syndrome.yaml`. The two share no mechanism and no overlapping presentation; the hazard is a literature or ontology search returning one for the other.

Distinguishing Features

Congenital joint contractures and cleft palate, with no electrolyte abnormality
Not caused by any of the four familial hyperkalemic hypertension genes

Show evidence (1 reference)

PMID:24266877 SUPPORT BACKGROUND Other

"FHHt (familial hyperkalaemic hypertension; also known as Gordon's syndrome) is a salt-dependent form of hypertension"

Documents that the renal syndrome carries the Gordon eponym, which is the source of the collision; quoted from the paper's framing rather than its results.

🐁

Animal Models

2

KLHL3 R528H knock-in mouse

A heterozygous knock-in of the recurrent dominant human Kelch-domain allele. It reproduces salt-sensitive hypertension, hyperkalemia and metabolic acidosis with raised renal WNK1, WNK4 and phosphorylated NCC, so it models the dominant form of the human disease at the level of both mechanism and phenotype.

Species

Mouse

Genotype

Klhl3 R528H/+ (heterozygous knock-in)

Publication

PMID:24821705

Pathograph links

WNK1 and WNK4 Kinase Accumulation recapitulates fidelity: high observes: molecular Both WNK substrates accumulate in the kidney of the heterozygous knock-in, and the mutant protein binds neither.

Readouts

Renal WNK1 and WNK4 protein abundance

Direction: INCREASED

Interpretation: Direct measurement of the accumulation this node asserts.

Show evidence (1 reference)

PMID:24821705 SUPPORT Model organism

"Interestingly, the protein expression of both WNK1 and WNK4 was significantly increased in the KLHL3(R528H/+) mouse kidney, confirming that increases in these WNK kinases activated the WNK-OSR1/SPAK-NCC phosphorylation cascade in KLHL3(R528H/+) knock-in mice."

Reports the raised renal WNK1 and WNK4 protein levels.

Show evidence (1 reference)

PMID:24821705 SUPPORT Model organism

"Thus, we found that increased protein expression levels of WNK1 and WNK4 kinases cause PHAII by KLHL3 R528H mutation due to impaired KLHL3-Cullin3-mediated ubiquitination."

The authors attribute the model's phenotype to the WNK accumulation this node names.

NCC Hyperphosphorylation in the Distal Convoluted Tubule recapitulates fidelity: high observes: organism Renal cotransporter phosphorylation is increased, with the salt-sensitive hypertension, hyperkalemia and acidosis that follow from it.

Limitations: The hypertension in the model is salt sensitive, that is, it needs a salt load to appear, whereas human carriers are hypertensive on an ordinary diet. One allele is modelled, so the recessive form and the allele-specific behaviour of S410L and the serine 433 substitutions are outside its scope.

Readouts

Renal phosphorylated NCC abundance

Direction: INCREASED

Interpretation: The phosphorylation state this node asserts, measured in the model kidney.

Show evidence (1 reference)

PMID:24821705 SUPPORT Model organism

"Moreover, the phosphorylation of NCC was increased in the KLHL3(R528H/+) mouse kidney, indicating that the KLHL3(R528H/+) knock-in mouse is an ideal mouse model of PHAII."

Reports increased renal cotransporter phosphorylation in the knock-in.

Show evidence (1 reference)

PMID:24821705 SUPPORT Model organism

"KLHL3(R528H/+) knock-in mice exhibited salt-sensitive hypertension, hyperkalemia and metabolic acidosis."

The model reproduces the three cardinal features of the human disease.

KLHL3 knockout mouse

A null allele carrying a beta-galactosidase reporter, which separates the two human inheritance modes experimentally. Homozygous nulls have the pseudohypoaldosteronism type II phenotype with raised renal WNK1 and WNK4; heterozygous nulls have neither. That asymmetry is the evidence that the dominant human alleles are dominant negative rather than haploinsufficient, and the reporter also shows where KLHL3 is expressed outside the kidney without WNK accumulating there.

Species

Mouse

Genotype

Klhl3-/- and Klhl3+/- (beta-galactosidase reporter knockout)

Publication

PMID:28052936

Pathograph links

Loss of KLHL3 Substrate Adaptor Function recapitulates fidelity: high observes: organism Complete loss of the adaptor produces the disease phenotype, and the review literature reads the homozygous null as the closest available model of the recessive human form.

Limitations: A null allele is not a missense allele: it cannot reproduce the dominant-negative heterodimer poisoning the human dominant alleles act through, which is precisely why the heterozygote is unaffected. No mouse carrying a recessive human missense allele has been reported.

Show evidence (2 references)

PMID:28052936 SUPPORT Model organism

"KLHL3-/- mice also showed PHAII-like phenotypes, whereas KLHL3+/- mice did not."

Complete adaptor loss gives the disease phenotype while a single null allele does not.

+ 1 more reference

Dominant-Negative Poisoning of KLHL3 Dimers fails to recapitulate fidelity: unknown observes: organism The heterozygous null does not develop the disease, so this model does not reproduce the dominant human phenotype. That negative result is the argument for the dominant-negative mechanism rather than a shortcoming of the experiment.

Limitations: A deletion removes the subunit instead of substituting it, so there is no mutant protein available to poison a dimer. The model therefore bounds the mechanism from one side only and cannot demonstrate the poisoning directly.

Divergences from the human mechanism

proxy quantity qualifying

The model's quantity is KLHL3 gene dose, halved by deletion. The node's quantity is the proportion of KLHL3 dimers carrying a mutant subunit, which a heterozygous missense allele raises while leaving gene dose intact. The two differ in the direction that matters here.

Show evidence (1 reference)

PMID:28052936 SUPPORT Model organism

"This clearly demonstrates that the heterozygous deletion of KLHL3 was not sufficient to cause PHAII, indicating that autosomal dominant type PHAII is caused by the dominant negative effect of mutant KLHL3."

The heterozygous null's lack of phenotype is what establishes the dominant-negative reading.

{ }

Source YAML

click to show

name: Pseudohypoaldosteronism Type 2D
category: Mendelian
creation_date: "2026-10-30T15:29:18Z"
synonyms:
- PHA2D
- PHAIID
- KLHL3 pseudohypoaldosteronism type 2
- pseudohypoaldosteronism type 2 caused by mutation in KLHL3
- KLHL3-related familial hyperkalemic hypertension
- Gordon syndrome due to KLHL3 mutation
description: >-
  Pseudohypoaldosteronism type 2D (PHA2D) is the KLHL3-related form of familial
  hyperkalemic hypertension, the syndrome also called pseudohypoaldosteronism
  type II or, in its renal sense, Gordon syndrome. KLHL3 is the substrate adaptor
  that presents the WNK1 and WNK4 kinases to a CUL3-RING E3 ubiquitin ligase for
  proteasomal degradation. When that presentation fails, WNK kinase protein
  accumulates in the distal convoluted tubule and drives the SPAK and OSR1
  cascade, which phosphorylates and activates the thiazide-sensitive sodium
  chloride cotransporter NCC (SLC12A3). The resulting constitutive distal sodium
  chloride reabsorption expands extracellular volume, producing hypertension and
  renin suppression, while diverting sodium away from the ENaC-expressing
  segments downstream removes the electrical driving force for potassium
  secretion. Excess WNK4 additionally suppresses the ROMK and BK potassium
  channels themselves, so patients are hyperkalemic despite a normal glomerular
  filtration rate and an aldosterone level that is inappropriately low for the
  degree of hyperkalemia. Hyperchloremia, hyperchloremic metabolic acidosis and
  hypercalciuria complete the biochemical picture. KLHL3 is the only one of the
  four familial hyperkalemic hypertension genes with both an autosomal dominant
  and an autosomal recessive form: recessive alleles are distributed through the
  protein and abolish adaptor function, whereas dominant alleles cluster in the
  Kelch propeller and BTB domains, where they block WNK or CUL3 binding and act
  as dominant negatives through KLHL3 dimerization. Thiazide diuretics, which
  inhibit the overactive cotransporter directly, correct the electrolyte and
  blood pressure abnormalities.
disease_term:
  preferred_term: pseudohypoaldosteronism type 2D
  term:
    id: MONDO:0013781
    label: pseudohypoaldosteronism type 2D
parents:
- Pseudohypoaldosteronism type 2
notes: >-
  Scope of the syndrome-level sources. The Orphanet record cited throughout
  (ORPHA:757, pseudohypoaldosteronism type 2) and the GeneReviews chapter
  (PMID:22073419) both describe pseudohypoaldosteronism type II across all four
  causative genes (WNK1, WNK4, KLHL3, CUL3) rather than the KLHL3 form alone, so
  their phenotype frequencies and their statement that prevalence is unknown
  apply to the syndrome as a whole. Figures specific to KLHL3 come from the
  Boyden cohort (PMID:22266938), whose genotype-stratified table reports its 8
  recessive and 16 dominant KLHL3 kindreds as separate rows.

  Name collision. `kb/disorders/Gordon_Syndrome.yaml` in this knowledge base is
  distal arthrogryposis type 3, an unrelated musculoskeletal disorder sharing
  the eponym. It is not a parent or a relative of this entry and appears under
  `differential_diagnoses` only to record the collision; the renal sense of
  Gordon syndrome is this disease and its sibling gene forms.

  Sibling gene forms. PHA2A (WNK1), PHA2B (WNK4) and PHA2E (CUL3) are separate
  MONDO concepts sharing this mechanism from the WNK accumulation step onwards.
  They are cited here as differential diagnoses; their pathophysiology is not
  duplicated in this entry.

  Several cited experiments were done in WNK4 D561A or constitutively active
  SPAK mice rather than in a KLHL3 genotype. They are used only where the claim
  is about the shared cascade downstream of WNK accumulation, which the KLHL3
  R528H knock-in independently shows is engaged, and each explanation says which
  genotype the result came from. No KLHL3-specific claim rests on them.

  Mechanism of the acidosis. No study has established it in a KLHL3 genotype.
  The constitutively active SPAK mouse, which isolates cotransporter
  hyperactivation, attributes it to a secondary effect of hyperkalemia on
  proximal tubule and collecting duct ammonia handling, and that is the chain
  encoded here. The WNK4 Q562E mouse supports a different account, excessive
  collecting duct bicarbonate secretion through pendrin, and a cohort of 18
  human WNK4 Q565E patients had renal ammonium excretion no lower than
  unaffected subjects. The disagreement is recorded as a knowledge gap rather
  than resolved in the pathograph.

  Muscle weakness, periodic paralysis, fatigue and nausea with vomiting are
  recorded as phenotypes but left unwired to the pathograph. The aldosterone row
  is unwired for the same reason: the cited sources state the paradox but none
  states what produces it, and the obvious reading, that volume expansion
  removes the angiotensin II drive while the potassium stimulus persists, is an
  inference no quoted source makes. They are
  clinically attributed to the hyperkalemia, and the entry's description says
  so, but no source found states that causal link for this syndrome: Orphanet
  lists the features without a mechanism, GeneReviews does not mention them,
  and the one PHA2D case report gives them as presenting complaints rather than
  as consequences of a measured potassium. A `sequelae` edge from Hyperkalemia
  would be the right encoding once such a source exists. The same holds for
  short stature and growth delay, where the only candidate source
  (PMID:41380172) reports normal growth in its own patient.

  GeneReviews describes hypercalciuria in four words, below the snippet-length
  floor, so that claim is cited from PMID:25925082 instead, which is also
  KLHL3-specific and quantitative. GeneReviews remains the entry's phenotype
  baseline and is tagged in `references`.

  Hypercalciuria is documented in KLHL3-mutant families (PMID:25925082) but is
  deliberately left unwired to the pathograph. The only mechanistic account in
  the literature comes from the WNK4 D561A mouse, a different genotype whose
  human counterpart has more severe hypercalciuria, so no causal edge from the
  cotransporter node is sourced for the KLHL3 form.

  No ClinGen gene-disease validity assertion exists for the KLHL3 and
  pseudohypoaldosteronism type 2D pair in the committed ClinGen export
  (`kb/genes/ingest/clingen_gene_validity.tsv` and
  `cache/clingen/gene_validity.csv` carry one for CUL3 with PHA2E only), so no
  `gene_disease_validity` record is copied into this entry.

  Three leads from the openscientist deep-research report were checked and not
  used. It gives KLHL3 as HGNC:15531, which is EBNA1BP2; the correct identifier,
  read from the HGNC REST record for the symbol, is hgnc:6354. It binds
  suppressed renin to HP:0040331, which HPO calls Focal hypointensity of cerebral
  white matter on MRI, and hyperchloremic metabolic acidosis to HP:0004910, which
  is Bicarbonate-wasting renal tubular acidosis; the terms used here
  (HP:0003351, HP:0004918) were resolved independently. And it cites
  PMID:41380172 for growth impairment, but that paper is a CUL3 case whose
  follow-up reports normal growth and appropriate developmental milestones, so it
  supports neither the growth claim nor anything about the KLHL3 form.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Heterozygous missense KLHL3 variants clustered in the Kelch propeller and
    BTB domains segregate with the trait under a dominant model. They are
    inferred to act as dominant negatives because they phenocopy recessive loss
    of function, and because mice heterozygous for a KLHL3 null allele are
    unaffected while a heterozygous R528H knock-in is not. KLHL3 dimerization
    supplies the mechanism: a mutant subunit disables the heterodimer it joins.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  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: "Sixteen kindreds have heterozygous mutations that co-segregate with the trait under a dominant model"
    explanation: Sixteen KLHL3 kindreds show dominant co-segregation of a heterozygous variant.
  - 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: "Importantly, we infer that mutations in dominant kindreds are likely dominant-negative, because they phenocopy the features of recessive disease."
    explanation: States the dominant-negative inference for the heterozygous KLHL3 alleles.
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "PHAII is frequently inherited in an autosomal dominant manner; PHAIID (caused by pathogenic variants in KLHL3) may also be inherited in an autosomal recessive manner."
    explanation: GeneReviews records both modes for the KLHL3 form specifically.
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Each child of an individual with autosomal dominant PHAII has a 50% chance of inheriting the pathogenic variant."
    explanation: Gives the recurrence risk this mode carries, which is what the counselling in `treatments` acts on.
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) in the family are known."
    explanation: Records that prenatal testing is available once the familial variant is identified.
- name: Autosomal recessive inheritance
  description: >-
    Biallelic KLHL3 variants, homozygous or compound heterozygous, cause the
    same disease in kindreds where affected members are confined to siblings who
    inherited both alleles while relatives carrying none or one are unaffected.
    Recessive alleles are distributed throughout the protein rather than
    clustered, and consanguinity underlies several of the reported families.
    Recessive transmission was unknown for pseudohypoaldosteronism type II
    before KLHL3 was identified, and KLHL3 remains the only familial
    hyperkalemic hypertension gene with a recessive form.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  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: "In these kindreds, affected members are confined to siblings of index cases who inherited the same two mutations, while unaffected relatives inherited zero or one mutation"
    explanation: Segregation in the eight biallelic KLHL3 kindreds follows a recessive model.
  - 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: "Recessive transmission has not been previously described for PHAII."
    explanation: Records that the recessive mode was first established through KLHL3.
  - reference: PMID:28511177
    reference_title: "Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A family with recessive FHHt caused by a new KLHL3 mutation, S553L, is described."
    explanation: An independent consanguineous family carrying a recessive KLHL3 allele.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequent genetic testing identified a novel homozygous splice-site mutation in the KLHL3, confirming autosomal recessive PHA2D."
    explanation: A homozygous splice-site KLHL3 variant in recessive PHA2D.
  - reference: PMID:39699086
    reference_title: "Familial Hyperkalemic Hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "KLHL3 mutations account for 50-60% of FHHt-causing mutations, and of these, about 25% are recessive and 75% are dominant"
    explanation: Gives the proportion of KLHL3 alleles that are recessive rather than dominant.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Orphanet records the point prevalence of pseudohypoaldosteronism type 2 as
    unknown across all four causative genes, and no KLHL3-specific figure
    exists. The published series give the scale rather than a rate: KLHL3
    variants were found in 24 index cases of a 52-kindred referral cohort, which
    is a referral denominator and not a population one.
  evidence:
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unknown | Worldwide | Point prevalence | PMID:22073419"
    explanation: Orphanet epidemiology row recording an unknown worldwide point prevalence.
  - 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 was sequenced in all PHAII index cases, identifying novel mutations in 24"
    explanation: Twenty-four of the 52 referred pseudohypoaldosteronism type II kindreds carried a KLHL3 variant.
progression:
- phase: Biochemical disease without hypertension
  age_range: Childhood to early adulthood
  notes: >-
    Hyperkalemia with hyperchloremic metabolic acidosis and suppressed renin
    typically precedes hypertension in the KLHL3 form. Only 14 percent of
    recessive and 17 percent of dominant KLHL3 patients were diagnosed with
    hypertension by age 18, against 94 percent for CUL3, and mean age at
    diagnosis or referral was in the mid twenties for both KLHL3 classes. A
    normotensive nine-year-old with biallelic KLHL3 disease has been reported in
    whom the absence of hypertension delayed diagnosis.
  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 Recessive | 8 | 14 | 26 ±14 | 6.8 ±0.5 | 17.6 ±1.5 | 14 |"
    explanation: Genotype-stratified row giving a mean diagnosis age of 26 years and 14 percent hypertensive by age 18 for recessive KLHL3.
  - 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: "Subjects with CUL3 mutations presented at much younger ages than those with mutation in KLHL3, WNK1, or WNK4, and had significantly more severe hyperkalemia and metabolic acidosis and were far more likely to have hypertension before age 18 (others commonly develop hypertension at later ages)"
    explanation: Hypertension in the KLHL3 form commonly appears later than in CUL3 disease.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory evaluation revealed severe hyperkalaemia and hyperchloremic metabolic acidosis with a normal glomerular filtration rate and persistent normotension."
    explanation: Documents the biochemical phase without hypertension in a child with PHA2D.
- phase: Hypertension and its complications
  age_range: Adulthood
  notes: >-
    Hypertension develops in most affected adults and carries the usual
    cardiovascular, renal and cerebrovascular risk, which is why blood pressure
    control is part of management rather than electrolyte correction alone.
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Control of blood pressure is important to reduce the risk of cardiovascular and renal disease and stroke."
    explanation: GeneReviews states the rationale for treating the hypertensive phase.
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: All ages"
    explanation: Orphanet records onset across all ages for pseudohypoaldosteronism type 2.
genetic:
- name: KLHL3
  association: Causative, autosomal dominant (dominant negative) or autosomal recessive (biallelic loss of function)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: KLHL3
    term:
      id: hgnc:6354
      label: KLHL3
  notes: >-
    KLHL3 encodes a BTB-BACK-Kelch protein serving as the substrate adaptor of a
    CUL3-RING E3 ubiquitin ligase. Two allele classes behave differently.
    Recessive alleles are spread through the protein and include a nonsense
    allele (W470X), a compound heterozygous missense pair (F322C with S410L), a
    homozygous splice-site allele, and homozygous S553L. Dominant alleles
    cluster: nine of sixteen in the Boyden series alter the d-a loops of the
    Kelch propeller and three sit in the BTB domain at sites implicated in
    cullin binding. S410L is mechanistically distinctive in combining reduced
    protein stability with reduced WNK4 affinity. S433G and S433N substitute the
    serine whose physiological phosphorylation normally switches WNK binding
    off, so those alleles mimic a constitutively phosphorylated adaptor.
  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: Identification of KLHL3 as a pseudohypoaldosteronism type II gene.
  - 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: "While recessive KLHL3 mutations are distributed throughout the encoded protein, dominant KLHL3 mutations show striking clustering"
    explanation: Contrasts the distribution of recessive and dominant KLHL3 alleles.
  - reference: PMID:22406640
    reference_title: "KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt."
    explanation: Independent identification of KLHL3 as a familial hyperkalemic hypertension gene.
  - reference: PMID:22406640
    reference_title: "KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance."
    explanation: Eleven further missense alleles with heterogeneous phenotype and mixed inheritance.
  - 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: "KLHL3 variants all occur in kelch-repeat domains and so probably disrupt WNK complex binding."
    explanation: A replication cohort in which every KLHL3 variant fell in a Kelch repeat.
  variants:
  - name: R528H
    description: >-
      Recurrent heterozygous Kelch-domain missense allele, the one modelled in
      knock-in mice. Mutant KLHL3 R528H binds neither WNK1 nor WNK4, and a
      CUL3-KLHL3 R528H complex fails to ubiquitylate WNK1 in vitro. Reported in
      dominant kindreds.
    evidence:
    - reference: PMID:24821705
      reference_title: "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we measured the binding of TAMRA-labeled WNK1 and WNK4 peptides to full-length KLHL3 using fluorescence correlation spectroscopy, and found that neither WNK1 nor WNK4 bound to mutant KLHL3 R528H"
      explanation: R528H abolishes binding of both WNK substrates.
    - reference: PMID:23387299
      reference_title: "The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The recombinant wild-type CUL3-KLHL3 E3 ligase complex, but not a disease-causing CUL3-KLHL3 ... mutant complex, ubiquitylated WNK1 in vitro."
      explanation: The R528H complex loses WNK1 ubiquitylation activity.
  - name: S410L
    description: >-
      Kelch-domain allele reported as one half of a compound heterozygous
      recessive genotype with F322C. It is distinctive in lowering KLHL3 protein
      stability as well as WNK4 binding affinity.
    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: "one in which affected members are compound heterozygotes for two missense mutations (F322C and S410L)"
      explanation: S410L occurs as one allele of a compound heterozygous recessive genotype.
    - reference: PMID:39699086
      reference_title: "Familial Hyperkalemic Hypertension."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "This indicated that the mechanism for the increase in WNK abundance was reduced stability of the KLHL3 S410L mutant protein."
      explanation: S410L raises WNK abundance by destabilising the adaptor, not only by losing binding.
  - name: W470X
    description: >-
      Homozygous nonsense allele in the kindred that first established recessive
      transmission of pseudohypoaldosteronism type II.
    variant_type: single nucleotide variant
    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: "These include one kindred in which affected members are homozygous for a nonsense mutation (W470X)"
      explanation: A homozygous nonsense KLHL3 allele in a recessive kindred.
  - name: S433G and S433N
    description: >-
      Kelch-domain alleles substituting serine 433, the residue whose
      phosphorylation by protein kinase C, protein kinase A or Akt normally
      prevents WNK binding. A molecular dynamics study shows the phosphate makes
      the acidic-motif binding pocket more electronegative and dismantles the
      hydrogen bond network holding WNK4 there, which is why these alleles are
      read as mimicking the phosphorylated adaptor rather than simply disabling
      it.
    evidence:
    - reference: PMID:39699086
      reference_title: "Familial Hyperkalemic Hypertension."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "FHHt-causing mutations S433G and S443N likely recapitulate the effect of bona fide phosphorylation of S433 or the phosphomimetic S433E mutation exerting significant structural changes that prevent WNK4 binding to the CUL3-KLHL3 CRL."
      explanation: Reads the serine 433 substitutions as phosphomimetic. The quoted sentence carries the review's own typographical slip in the second allele name; the correct allele is S433N, as the preceding sentence of that paragraph gives it.
    - reference: PMID:27727489
      reference_title: "Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "In conclusion, phosphorylation of KLHL3 at S433 disrupts the hydrogen bonds, hydrophobic and electrostatic interactions between the Kelch domain of KLHL3 and the AM of WNK4."
      explanation: Supplies the structural account of why a modification or substitution at serine 433 abolishes WNK4 binding.
    - reference: PMID:27727489
      reference_title: "Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "phosphorylation of KLHL3 at serine 433, which is also a site frequently mutated in patients"
      explanation: Confirms that serine 433 is both the regulatory site and a recurrent patient mutation site.
  - name: S553L
    description: >-
      Homozygous allele in a consanguineous Jewish family of Yemenite origin,
      one of the few reported recessive KLHL3 genotypes outside the original
      series. Its biochemistry has not been characterised.
    evidence:
    - reference: PMID:28511177
      reference_title: "Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This consanguineous Jewish family of Yemenite extraction, included 2 homozygous and 7 heterozygous affected subjects."
      explanation: Records the homozygous S553L genotype and the family it was found in.
  - name: Q309R
    description: >-
      Recurrent heterozygous Kelch-domain allele reported in dominant kindreds,
      including the family in which raised urinary exosomal NCC abundance was
      first shown, and one of the two families in which hypercalciuria was
      quantified.
    evidence:
    - reference: PMID:25925082
      reference_title: "Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two new families with FHHt including a total number of 23 subjects, 10 of them affected, in whom previously described mutations in KLHL3 (Q309R and R528H) were identified."
      explanation: Q309R and R528H were the alleles in the two families studied for hypercalciuria.
    - reference: PMID:28511177
      reference_title: "Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Increased urinary NCC was found in the affected members of the family with dominant Q309R KLHL3 mutation."
      explanation: Q309R carriers showed the raised urinary cotransporter abundance the mechanism predicts.
pathophysiology:
- name: Dominant-Negative Poisoning of KLHL3 Dimers
  description: >-
    Heterozygous KLHL3 missense alleles in the Kelch propeller and BTB domains
    do not merely halve adaptor dose. KLHL3 dimerizes, so a mutant subunit
    disables the heterodimer it joins and only wild-type homodimers remain
    functional. The genetic evidence is an asymmetry in mice: heterozygotes for
    a KLHL3 null allele are unaffected and accumulate no renal WNK, whereas
    heterozygous human missense carriers and heterozygous R528H knock-in mice
    have the full phenotype.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: KLHL3
    term:
      id: hgnc:6354
      label: KLHL3
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: DOMINANT_NEGATIVE
  downstream:
  - target: Loss of KLHL3 Substrate Adaptor Function
    causal_link_type: DIRECT
    description: >-
      Poisoned heterodimers leave the CUL3-KLHL3 complex unable to present its
      WNK substrates, the same end state as biallelic loss.
    evidence:
    - reference: PMID:28052936
      reference_title: "KLHL3 Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We further demonstrated that the dimerization of KLHL3 can explain this dominant negative effect."
      explanation: Links dimerization to the dominant-negative behaviour of mutant KLHL3.
  evidence:
  - reference: PMID:28052936
    reference_title: "KLHL3 Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This clearly demonstrates that the heterozygous deletion of KLHL3 was not sufficient to cause PHAII, indicating that autosomal dominant type PHAII is caused by the dominant negative effect of mutant KLHL3."
    explanation: Heterozygous null mice are unaffected, so the dominant human alleles must act as dominant negatives.
  - 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: "Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates."
    explanation: The dominant alleles phenocopy recessive loss of function, the original argument for a dominant-negative mechanism.
- name: KLHL3 Serine 433 Phosphorylation Blocking WNK Binding
  description: >-
    Phosphorylation of KLHL3 at serine 433, inside the Kelch domain, prevents
    WNK4 from binding and so prevents its degradation. This is the physiological
    switch by which angiotensin II, dietary potassium restriction, insulin and
    vasopressin signalling raise WNK levels, and calcineurin reverses it. The
    disease alleles S433G and S433N occupy that residue, so PHA2D includes a
    genetic lock of a normally regulated switch. The same node explains why
    calcineurin inhibitors produce an acquired phenocopy.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: KLHL3
    term:
      id: hgnc:6354
      label: KLHL3
  biological_processes:
  - preferred_term: KLHL3 serine 433 phosphorylation
    modifier: INCREASED
    term:
      id: GO:0006468
      label: protein phosphorylation
  downstream:
  - target: Loss of KLHL3 Substrate Adaptor Function
    causal_link_type: DIRECT
    description: >-
      Serine 433 phosphorylation, or its genetic mimicry, abolishes substrate
      binding without changing adaptor abundance.
    evidence:
    - reference: PMID:25313067
      reference_title: "Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation."
      explanation: States directly that serine 433 phosphorylation blocks WNK4 binding and degradation.
  evidence:
  - reference: PMID:25313067
    reference_title: "Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "AII administration to mice, even in the absence of volume depletion, induces renal KLHL3(S433) phosphorylation and increased levels of both WNK4 and the NaCl cotransporter."
    explanation: Angiotensin II drives the same serine 433 phosphorylation in vivo with the expected WNK4 and cotransporter response.
  - reference: PMID:26435498
    reference_title: "Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In conclusion, we found that Akt and PKA phosphorylated KLHL3 at S433, and phosphorylation of KLHL3 by PKA inhibited WNK4 degradation."
    explanation: Protein kinase A and Akt converge on the same residue, placing insulin and vasopressin signalling on this node.
  - reference: PMID:27942049
    reference_title: "Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the distal convoluted tubules of mice eating a low-K+ diet, we found increased KLHL3 phosphorylation at S433 (KLHL3S433-P), a modification that impairs WNK binding, and also reduced total KLHL3 levels."
    explanation: Dietary potassium restriction uses the same switch in the distal convoluted tubule.
  - reference: PMID:30718414
    reference_title: "Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vivo, tacrolimus increases levels of KLHL3S433-P, resulting in increased levels of WNK4, phosphorylated SPAK, and NCC."
    explanation: Calcineurin inhibition raises serine 433 phosphorylation and reproduces the downstream cascade.
  - reference: PMID:27727489
    reference_title: "Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Results from independent simulations indicate that when S433 was phosphorylated, the electrostatic potential became more negative in the AM binding site of KLHL3 and therefore was unfavorable for binding with the negatively charged AM."
    explanation: Gives the electrostatic basis for the loss of binding at this node.
- name: Loss of KLHL3 Substrate Adaptor Function
  description: >-
    KLHL3 is the BTB-BACK-Kelch substrate adaptor that recruits WNK kinases to a
    CUL3-based ubiquitin ligase complex. Disease alleles remove that function by
    three converging routes: abolished WNK binding through the Kelch propeller,
    abolished CUL3 binding through the BTB domain, and in the S410L case reduced
    adaptor stability. The protein is expressed where the disease acts,
    predominantly in the distal convoluted tubule and collecting duct with
    apical localization in the distal convoluted tubule.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: KLHL3
    term:
      id: hgnc:6354
      label: KLHL3
  molecular_functions:
  - preferred_term: KLHL3 ubiquitin ligase substrate adaptor activity
    modifier: DECREASED
    term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
  cell_types:
  - preferred_term: kidney distal convoluted tubule epithelial cell
    term:
      id: CL:1000849
      label: kidney distal convoluted tubule epithelial cell
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Failed CUL3-KLHL3 Ubiquitination of WNK Kinases
    causal_link_type: DIRECT
    description: >-
      Without a functional adaptor the ligase complex cannot ubiquitylate its
      WNK substrates.
    evidence:
    - reference: PMID:23387299
      reference_title: "The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Strikingly, 13 out of the 15 dominant KLHL3 disease mutations analysed inhibited binding to WNK1 or CUL3."
      explanation: Nearly every dominant allele tested breaks one of the two interactions the adaptor needs.
  evidence:
  - reference: PMID:23665031
    reference_title: "Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We conclude that KLHL3 is a substrate adaptor for WNK4 in a ubiquitin E3 ligase complex."
    explanation: Establishes the adaptor role that disease alleles remove.
  - reference: PMID:23665031
    reference_title: "Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All five PHAII mutations of KLHL3 tested disrupted the regulation on WNK4."
    explanation: Every disease allele tested lost the regulatory effect on WNK4.
  - reference: PMID:22406640
    reference_title: "KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes."
    explanation: Places KLHL3 in the substrate-recruiting family for CUL3 ligases.
  - reference: PMID:22266938
    reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "KLHL3 is predominantly expressed in DCT and CD, with apical localization in DCT"
    explanation: Expression is concentrated in the nephron segments where the disease acts.
- name: Failed CUL3-KLHL3 Ubiquitination of WNK Kinases
  description: >-
    The wild-type CUL3-KLHL3 complex polyubiquitylates WNK1 and WNK4, tagging
    them for proteasomal destruction; at least fifteen ubiquitination sites have
    been mapped in WNK4. Loss of adaptor function removes that tag.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: WNK kinase ubiquitination by the CUL3-KLHL3 complex
    modifier: DECREASED
    term:
      id: GO:0016567
      label: protein ubiquitination
  cellular_components:
  - preferred_term: Cul3-RING ubiquitin ligase complex
    term:
      id: GO:0031463
      label: Cul3-RING ubiquitin ligase complex
  downstream:
  - target: WNK1 and WNK4 Kinase Accumulation
    causal_link_type: DIRECT
    description: >-
      Untagged WNK kinase escapes proteasomal degradation, so its steady-state
      protein level rises.
    evidence:
    - reference: PMID:23453970
      reference_title: "Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein."
      explanation: States the step from failed ubiquitination to raised WNK4 protein.
    - reference: PMID:26152401
      reference_title: "Kelch-like 3/Cullin 3 ubiquitin ligase complex and WNK signaling in salt-sensitive hypertension and electrolyte disorder."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In PHAII, the loss of interaction between KLHL3 and WNK4 induces increased levels of WNK kinases due to impaired ubiquitination."
      explanation: The review states the same edge as the field's settled reading.
  evidence:
  - reference: PMID:23576762
    reference_title: "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that this binding leads to ubiquitination, including polyubiquitination, of at least 15 specific sites in WNK4, resulting in reduced WNK4 levels."
    explanation: Maps the ubiquitination the complex normally performs on WNK4.
  - reference: PMID:23576762
    reference_title: "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Dominant disease-causing mutations in KLHL3 and WNK4 both impair WNK4 binding, ubiquitination, and degradation."
    explanation: Disease alleles in both genes converge on this failed ubiquitination step.
  - reference: PMID:23387299
    reference_title: "The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, siRNA (small interfering RNA)-mediated knockdown of CUL3 increased WNK1 protein levels and kinase activity in HeLa cells."
    explanation: Removing the ligase scaffold raises WNK1 protein and kinase activity, the expected consequence of losing the complex.
  - reference: PMID:26349538
    reference_title: "Involvement of selective autophagy mediated by p62/SQSTM1 in KLHL3-dependent WNK4 degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Thus, WNK4 was degraded not only by proteasomes but also by p62-KLHL3-mediated selective autophagy, which may be involved in WNK regulation under certain pathophysiological conditions."
    explanation: A second, autophagic route for KLHL3-directed WNK4 disposal, which the same adaptor loss removes.
- name: WNK1 and WNK4 Kinase Accumulation
  description: >-
    Both WNK substrates accumulate in the kidney when the adaptor fails, and the
    accumulation is kidney-restricted even though KLHL3 is expressed elsewhere.
    This is the point at which the KLHL3 and CUL3 forms of the disease join the
    WNK1 and WNK4 forms, where variants in the kinases themselves produce the
    same excess of WNK activity.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: WNK1
    term:
      id: hgnc:14540
      label: WNK1
  - preferred_term: WNK4
    term:
      id: hgnc:14544
      label: WNK4
  biological_processes:
  - preferred_term: proteasomal degradation of WNK kinases
    modifier: DECREASED
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
  downstream:
  - target: SPAK and OSR1 Hyperactivation
    causal_link_type: DIRECT
    description: >-
      Excess WNK kinase phosphorylates and activates its downstream kinases SPAK
      and OSR1.
    evidence:
    - reference: PMID:24821705
      reference_title: "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Interestingly, the protein expression of both WNK1 and WNK4 was significantly increased in the KLHL3(R528H/+) mouse kidney, confirming that increases in these WNK kinases activated the WNK-OSR1/SPAK-NCC phosphorylation cascade in KLHL3(R528H/+) knock-in mice."
      explanation: In the KLHL3 knock-in model, raised WNK protein activates the OSR1 and SPAK cotransporter cascade.
  - target: WNK4-Mediated Suppression of ROMK and BK Channels
    causal_link_type: DIRECT
    description: >-
      Separately from its action on the cotransporter, excess WNK4 acts directly
      on the secretory potassium channels of the downstream segments, so this
      branch of the mechanism does not run through NCC.
    evidence:
    - reference: PMID:23885063
      reference_title: "Regulation of large-conductance Ca2+-activated K+ channels by WNK4 kinase."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "With-no-lysine kinase 4 (WNK4) is a serine-threonine kinase expressed in the distal nephron that inhibits ROMK activity and renal K(+) secretion."
      explanation: Excess WNK4 acts on the distal secretory machinery itself, not only through the cotransporter.
  evidence:
  - reference: PMID:28052936
    reference_title: "KLHL3 Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the expression levels of WNK kinases were not increased in any of these organs other than the kidney, where WNK1 and WNK4 increased in KLHL3-/- mice but not in KLHL3+/- mice"
    explanation: WNK accumulation on loss of KLHL3 is confined to the kidney.
  - reference: PMID:39699086
    reference_title: "Familial Hyperkalemic Hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "CUL3 and KLHL3 are now known to form a ubiquitin ligase complex that promotes proteasomal degradation of WNK kinases, which activate downstream kinases that phosphorylate and thus activate NCC."
    explanation: States the whole adaptor-to-cotransporter chain in which this node is the middle step.
- name: SPAK and OSR1 Hyperactivation
  description: >-
    The WNK kinases act on the cotransporter through two closely related
    kinases, SPAK (STK39) and OSR1 (OXSR1), which phosphorylate NCC directly.
    Genetic epistasis in the WNK4 D561A mouse shows this cascade is not merely
    correlated with the disease but required for it: deleting Spak abolished the
    phenotype, kidney-specific Osr1 deletion did not, and knock-ins preventing
    WNK-mediated activation of both kinases corrected the whole triad. SPAK is
    therefore the principal effector.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: STK39
    term:
      id: hgnc:17717
      label: STK39
  - preferred_term: OXSR1
    term:
      id: hgnc:8508
      label: OXSR1
  molecular_functions:
  - preferred_term: SPAK and OSR1 protein serine/threonine kinase activity
    modifier: INCREASED
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
  downstream:
  - target: NCC Hyperphosphorylation in the Distal Convoluted Tubule
    causal_link_type: DIRECT
    description: >-
      SPAK and OSR1 phosphorylate the sodium chloride cotransporter, which
      activates it and promotes its accumulation at the apical membrane.
    evidence:
    - reference: PMID:27942049
      reference_title: "Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These changes are accompanied by the accumulation of the target substrate WNK4, and activation of the downstream kinases SPAK (STE20/SPS1-related proline-alanine-rich protein kinase) and OSR1 (oxidative stress-responsive 1), resulting in NCC phosphorylation and its accumulation at the plasma membrane."
      explanation: Traces SPAK and OSR1 activation to cotransporter phosphorylation and membrane accumulation.
    - reference: PMID:21486947
      reference_title: "Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found that NCC phosphorylation was almost completely abolished in Wnk4(D561A/+)Spak(T)(243A/T243A)Osr1(T185A/+) triple knock-in mice, clearly demonstrating that NCC phosphorylation in vivo is dependent on the WNK-OSR1/SPAK cascade."
      explanation: Blocking activation of both kinases abolishes cotransporter phosphorylation in vivo. Shown in the WNK4 D561A mouse, which shares this cascade with the KLHL3 form rather than being a KLHL3 genotype.
  evidence:
  - reference: PMID:29361671
    reference_title: "Mechanisms and controversies in mutant Cul3-mediated familial hyperkalemic hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "proteasomal degradation of WNKs is abrogated, leading to overactivation of the WNK targets sterile 20/SPS-1 related proline/alanine-rich kinase and oxidative stress-response kinase-1, which directly phosphorylate and activate the thiazide-sensitive Na+-Cl- cotransporter"
    explanation: Names SPAK and OSR1 as the kinases that directly phosphorylate and activate the cotransporter downstream of failed WNK degradation. Written of the CUL3 form, which shares this cascade with the KLHL3 one.
  - reference: PMID:24039833
    reference_title: "SPAK deficiency corrects pseudohypoaldosteronism II caused by WNK4 mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Wnk4 (D561A/+).KSP-Osr1 (-/-) remained phenotypically PHA II while Wnk4 (D561A/+).Spak (-/-) mice became normotensive and lacked the PHA II phenotype."
    explanation: Identifies SPAK rather than OSR1 as the kinase whose loss rescues the phenotype. Shown in the WNK4 D561A mouse, which shares this cascade with the KLHL3 form.
  - reference: PMID:21486947
    reference_title: "Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the high blood pressure, hyperkalemia and metabolic acidosis observed in Wnk4(D561A/+) mice were corrected in the triple knock-in mice"
    explanation: The whole clinical triad depends on this cascade being activatable. Again in the WNK4 genotype, cited for the shared cascade rather than for KLHL3.
- name: NCC Hyperphosphorylation in the Distal Convoluted Tubule
  description: >-
    Phosphorylated NCC accumulates at the apical membrane of the distal
    convoluted tubule, raising its sodium chloride transport activity. KLHL3
    normally acts on this step from the other side as well, by downregulating
    the cotransporter at the cell surface. The excess is measurable in patients
    as raised urinary exosomal NCC abundance.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: kidney distal convoluted tubule epithelial cell
    term:
      id: CL:1000849
      label: kidney distal convoluted tubule epithelial cell
  genes:
  - preferred_term: SLC12A3
    term:
      id: hgnc:10912
      label: SLC12A3
  molecular_functions:
  - preferred_term: NCC sodium:chloride symporter activity
    modifier: INCREASED
    term:
      id: GO:0015378
      label: sodium:chloride symporter activity
  downstream:
  - target: Increased Distal Nephron Sodium Chloride Reabsorption
    causal_link_type: DIRECT
    description: >-
      An activated cotransporter at the apical membrane moves more sodium and
      chloride out of the tubular lumen.
    evidence:
    - reference: PMID:42057493
      reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This overactivity promotes excessive sodium and chloride reabsorption, resulting in hyperkalaemia, hyperchloremic metabolic acidosis, and suppressed renin/aldosterone levels, despite preserved renal function."
      explanation: States the step from cotransporter overactivity to excessive sodium and chloride reabsorption in PHA2D.
  evidence:
  - reference: PMID:24821705
    reference_title: "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, the phosphorylation of NCC was increased in the KLHL3(R528H/+) mouse kidney, indicating that the KLHL3(R528H/+) knock-in mouse is an ideal mouse model of PHAII."
    explanation: Cotransporter phosphorylation is raised in the kidney of the KLHL3 disease model.
  - reference: PMID:22406640
    reference_title: "KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface."
    explanation: KLHL3 normally restrains cotransporter surface expression in the same cells.
  - reference: PMID:28511177
    reference_title: "Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased urinary NCC was found in the affected members of the family with dominant Q309R KLHL3 mutation."
    explanation: Raised urinary exosomal cotransporter abundance confirms the excess in KLHL3 patients.
- name: Increased Distal Nephron Sodium Chloride Reabsorption
  description: >-
    Constitutive sodium chloride reabsorption in the distal convoluted tubule,
    independent of volume status, is the primary physiological defect of the
    syndrome. Two consequences follow: the retained salt expands extracellular
    volume, and sodium that would otherwise travel on to the ENaC-expressing
    segments is captured upstream. Chloride is retained with it, which the older
    name chloride shunt syndrome records.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: renal sodium ion absorption
    modifier: INCREASED
    term:
      id: GO:0070294
      label: renal sodium ion absorption
  locations:
  - preferred_term: distal convoluted tubule
    term:
      id: UBERON:0001292
      label: distal convoluted tubule
  downstream:
  - target: Volume Expansion with Renin Suppression
    causal_link_type: DIRECT
    description: Retained sodium chloride expands the extracellular fluid volume.
  - target: Reduced Sodium Delivery to ENaC-Expressing Segments
    causal_link_type: DIRECT
    description: >-
      Sodium captured in the distal convoluted tubule does not reach the
      downstream segments where it would drive potassium secretion.
    evidence:
    - reference: PMID:39699086
      reference_title: "Familial Hyperkalemic Hypertension."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "increased NCC activity and the subsequent increase in Na+ reabsorption lowers the delivery to the downstream segments that require Na+ entry through ENaC to drive K+ secretion"
      explanation: States the diversion of sodium away from the ENaC-expressing segments.
  - target: Hyperchloremia
    causal_link_type: DIRECT
    description: >-
      The cotransporter carries chloride with sodium, so chloride is retained
      alongside it.
  evidence:
  - reference: PMID:39699086
    reference_title: "Familial Hyperkalemic Hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The primary defect for most forms of FHHt is increased activity of the renal thiazide-sensitive NaCl cotransporter (NCC) expressed along the distal convoluted tubule"
    explanation: Identifies raised distal cotransporter activity as the primary defect of the syndrome.
  - 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: "constitutively increased salt reabsorption in the distal nephron regardless of volume status"
    explanation: Describes the volume-independent character of the salt reabsorption this pathway produces.
- name: Volume Expansion with Renin Suppression
  description: >-
    Salt retention expands the extracellular volume, which raises blood pressure
    and suppresses renin release. Suppressed renin is what separates this
    syndrome from the salt-wasting pseudohypoaldosteronism type 1 disorders, in
    which renin is high, and the resulting aldosterone level is inappropriately
    low for the degree of hyperkalemia, which is where the name comes from.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: regulation of blood pressure
    modifier: INCREASED
    term:
      id: GO:0008217
      label: regulation of blood pressure
  downstream:
  - target: Hypertension
    causal_link_type: DIRECT
    description: Volume expansion from retained sodium chloride raises arterial pressure.
    evidence:
    - reference: PMID:39699086
      reference_title: "Familial Hyperkalemic Hypertension."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Hypertension results from increased NaCl retention, and hyperkalemia by impaired K + secretion by downstream nephron segments."
      explanation: Attributes the hypertension to sodium chloride retention and the hyperkalemia to impaired distal secretion.
  - target: Suppressed plasma renin
    causal_link_type: DIRECT
    description: Volume expansion suppresses renin release.
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels."
    explanation: Records suppressed renin as part of the syndrome's profile.
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion)."
    explanation: Explains the inappropriately low aldosterone that gives the syndrome its name.
- name: Reduced Sodium Delivery to ENaC-Expressing Segments
  description: >-
    In the late distal convoluted tubule, connecting tubule and cortical
    collecting duct, ENaC-mediated sodium reabsorption generates the lumen
    negative voltage that drives potassium secretion through ROMK. When upstream
    NCC captures the sodium, less of it reaches these segments and that driving
    force is lost. This node carries the driving-force half of the potassium
    defect only; the suppression of the channels themselves is a separate branch
    out of WNK accumulation and has its own node.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: kidney collecting duct principal cell
    term:
      id: CL:1001431
      label: kidney collecting duct principal cell
  biological_processes:
  - preferred_term: renal sodium ion transport in ENaC-expressing segments
    modifier: DECREASED
    term:
      id: GO:0003096
      label: renal sodium ion transport
  downstream:
  - target: Impaired Distal Potassium Secretion
    causal_link_type: DIRECT
    description: >-
      Without ENaC-driven sodium entry there is no electrical driving force for
      luminal potassium secretion.
    evidence:
    - reference: PMID:39699086
      reference_title: "Familial Hyperkalemic Hypertension."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In these segments, ENaC-mediated Na+ reabsorption generates the electrical driving force for ROMK-mediated K+ secretion into the tubule lumen."
      explanation: States the electrical coupling between ENaC sodium entry and ROMK potassium secretion, which is the driving force this edge says is lost.
  evidence:
  - reference: PMID:39699086
    reference_title: "Familial Hyperkalemic Hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "increased NCC activity and the subsequent increase in Na+ reabsorption lowers the delivery to the downstream segments that require Na+ entry through ENaC to drive K+ secretion"
    explanation: States the reduced sodium delivery to these segments that is this node's own claim.
- name: WNK4-Mediated Suppression of ROMK and BK Channels
  description: >-
    Accumulated WNK4 lowers the secretory potassium channels of the distal
    segments directly, independently of anything happening to NCC. It clears the
    renal outer medullary potassium channel ROMK from the cell surface, an effect
    wild-type but not mutant KLHL3 restrains, and it reduces the
    large-conductance calcium-activated BK channel by promoting its degradation.
    So the segment loses the channels that would carry potassium out as well as
    the electrical driving force to push it.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: kidney collecting duct principal cell
    term:
      id: CL:1001431
      label: kidney collecting duct principal cell
  - preferred_term: kidney collecting duct intercalated cell
    term:
      id: CL:1001432
      label: kidney collecting duct intercalated cell
  genes:
  - preferred_term: WNK4
    term:
      id: hgnc:14544
      label: WNK4
  - preferred_term: KCNJ1
    term:
      id: hgnc:6255
      label: KCNJ1
  - preferred_term: KCNMA1
    term:
      id: hgnc:6284
      label: KCNMA1
  molecular_functions:
  - preferred_term: ROMK and BK potassium channel activity
    modifier: DECREASED
    term:
      id: GO:0005267
      label: potassium channel activity
  downstream:
  - target: Impaired Distal Potassium Secretion
    causal_link_type: DIRECT
    description: >-
      Fewer ROMK and BK channels at the apical membrane means less potassium can
      be secreted for any given driving force.
    evidence:
    - reference: PMID:23885063
      reference_title: "Regulation of large-conductance Ca2+-activated K+ channels by WNK4 kinase."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Based on these results, we propose that WNK4 provides a cellular mechanism for the coordinated regulation of two key secretory K(+) channels in the distal nephron."
      explanation: Places WNK4's action on both channels as the coordinated regulator of distal potassium secretion.
  evidence:
  - reference: PMID:23576762
    reference_title: "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "WNK4 normally induces clearance of the renal outer medullary K+ channel (ROMK) from the cell surface."
    explanation: Establishes the WNK4 effect on ROMK that this node asserts.
  - reference: PMID:23576762
    reference_title: "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that WT but not mutant KLHL3 inhibits WNK4-induced reduction of ROMK level."
    explanation: Mutant KLHL3 fails to restrain that effect, which is what ties this node to the disease rather than to normal physiology.
  - reference: PMID:23885063
    reference_title: "Regulation of large-conductance Ca2+-activated K+ channels by WNK4 kinase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our results suggest that WNK4 inhibits BK channel activity, in part, by increasing channel degradation through an ubiquitin-dependent pathway."
    explanation: Excess WNK4 also lowers the BK channel, the other secretory potassium route of these segments.
  - reference: PMID:21613417
    reference_title: "WNK4 kinase inhibits Maxi K channel activity by a kinase-dependent mechanism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These findings suggest that WNK4 WT inhibits Maxi K activity by reducing Maxi K protein at the membrane, but that the inhibition is not due to an increase in clathrin-mediated endocytosis of Maxi K, but likely due to enhancing its lysosomal degradation."
    explanation: Independent confirmation of the WNK4 effect on the BK channel, with the degradative route identified.
- name: Impaired Distal Potassium Secretion
  description: >-
    Renal potassium excretion falls despite a normal glomerular filtration rate
    and a potassium load that would normally drive secretion, producing the
    hyperkalemia that defines the syndrome.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: renal potassium excretion
    modifier: DECREASED
    term:
      id: GO:0036359
      label: renal potassium excretion
  downstream:
  - target: Hyperkalemia
    causal_link_type: DIRECT
    description: >-
      Potassium that cannot be secreted into the tubular lumen accumulates in
      the extracellular fluid.
    evidence:
    - reference: PMID:39699086
      reference_title: "Familial Hyperkalemic Hypertension."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "This results in lower K+ secretion and thus hyperkalemia."
      explanation: States the step from reduced potassium secretion to hyperkalemia.
  - target: Hyperkalemia-Driven Impairment of Renal Ammonium Excretion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The hyperkalemia that follows from the secretory defect is in turn what
      disturbs renal ammonia handling, in the account this entry encodes.
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension."
    explanation: Records that the hyperkalemia occurs with a preserved filtration rate, so it is a secretory defect.
  - reference: PMID:25313067
    reference_title: "Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "components of an E3 ubiquitin ligase complex that targets WNKs for degradation--cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia"
    explanation: Frames impaired potassium secretion as the shared human consequence of mutations in the complex; quoted from this paper's introduction rather than from its own cell and mouse experiments.
- name: Hyperkalemia-Driven Impairment of Renal Ammonium Excretion
  description: >-
    The metabolic acidosis of this syndrome is best explained as a secondary
    consequence of the hyperkalemia rather than as a primary proton secretion
    defect. In the constitutively active SPAK mouse, which isolates cotransporter
    hyperactivation from any other effect of the disease genes, correcting the
    hyperkalemia with a thiazide or with dietary potassium restriction also
    corrected the acidosis, and the mice showed reduced ammonia-generating
    enzymes in the proximal tubule with reduced collecting duct ammonia
    transport.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: renal ammonium homeostasis
    modifier: DECREASED
    term:
      id: GO:0097272
      label: ammonium homeostasis
  downstream:
  - target: Hyperchloremic metabolic acidosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced renal ammonium excretion lowers net acid excretion, producing the
      hyperchloremic acidosis.
    evidence:
    - reference: PMID:39699086
      reference_title: "Familial Hyperkalemic Hypertension."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Thus, metabolic acidosis in FHHt occurs due to secondary effects of hyperkalemia on ammonia metabolism and/or secretion along the proximal tubule and collecting duct."
      explanation: States the conclusion that the acidosis is secondary to hyperkalemia through ammonia handling.
  evidence:
  - reference: PMID:39699086
    reference_title: "Familial Hyperkalemic Hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Hydrochlorothiazide administration and dietary K+ restriction, both of which corrected hyperkalemia, also corrected metabolic acidosis in CA-SPAK mice."
    explanation: Correcting the hyperkalemia corrects the acidosis in the model that isolates cotransporter hyperactivation.
phenotypes:
- category: Metabolic/Laboratory
  name: Hyperkalemia
  frequency: VERY_FREQUENT
  description: >-
    The defining and most consistent finding, present despite a normal
    glomerular filtration rate. Mean serum potassium was 6.8 mmol/L in the
    recessive KLHL3 kindreds and 6.2 mmol/L in the dominant ones, against a
    normal range of 3.5 to 5.0.
  phenotype_term:
    preferred_term: Hyperkalemia
    term:
      id: HP:0002153
      label: Hyperkalemia
  evidence:
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002153 | Hyperkalemia | Very frequent (99-80%)"
    explanation: Orphanet records hyperkalemia as very frequent in pseudohypoaldosteronism type 2.
  - 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 Dominant | 16 | 40 | 24 ±18 | 6.2 ±0.6 | 17.2 ±2.5 | 17 |"
    explanation: Genotype-stratified mean serum potassium of 6.2 mmol/L in the dominant KLHL3 kindreds.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory evaluation revealed severe hyperkalaemia and hyperchloremic metabolic acidosis with a normal glomerular filtration rate and persistent normotension."
    explanation: Severe hyperkalemia with a normal filtration rate in a patient with biallelic KLHL3 disease.
- category: Cardiovascular
  name: Hypertension
  frequency: FREQUENT
  description: >-
    Usual but not invariable, and typically later in onset than in the CUL3
    form: only 17 percent of dominant and 14 percent of recessive KLHL3 patients
    were hypertensive by age 18. Normotensive PHA2D is reported and delays
    diagnosis. The frequency band follows the KLHL3-specific numbers rather than
    Orphanet's grading, which is `Very frequent (99-80%)` for the syndrome across
    all four genes: hypertension was present in 71 percent of the whole
    pseudohypoaldosteronism type II referral cohort, which is inside the
    `FREQUENT` band.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000822 | Hypertension | Very frequent (99-80%)"
    explanation: Orphanet records hypertension as very frequent in pseudohypoaldosteronism type 2.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case underscores that normotension in PHA2D may delay diagnosis and that standard thiazide dosing may precipitate hypotension in previously normotensive patients, necessitating highly individualized treatment strategies."
    explanation: Documents that hypertension can be absent in PHA2D.
- category: Metabolic/Laboratory
  name: Hyperchloremic metabolic acidosis
  frequency: VERY_FREQUENT
  description: >-
    Mean serum bicarbonate was 17.6 mmol/L in the recessive and 17.2 mmol/L in
    the dominant KLHL3 kindreds, against a normal range of 22 to 28, and
    acidosis was present in 82 percent of the whole pseudohypoaldosteronism type
    II referral cohort.
  phenotype_term:
    preferred_term: Hyperchloremic metabolic acidosis
    term:
      id: HP:0004918
      label: Hyperchloremic metabolic acidosis
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels."
    explanation: GeneReviews records hyperchloremia with metabolic acidosis as part of the syndrome.
  - 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: "hypertension and acidosis were present in 71% and 82%, respectively"
    explanation: Acidosis was present in 82 percent of the referral cohort from which the KLHL3 kindreds were drawn.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This overactivity promotes excessive sodium and chloride reabsorption, resulting in hyperkalaemia, hyperchloremic metabolic acidosis, and suppressed renin/aldosterone levels, despite preserved renal function."
    explanation: Names hyperchloremic metabolic acidosis as a core feature of PHA2D.
- category: Metabolic/Laboratory
  name: Hyperchloremia
  description: >-
    Chloride is retained with sodium by the overactive cotransporter. The older
    name chloride shunt syndrome, which Orphanet still lists as a synonym,
    records this feature.
  phenotype_term:
    preferred_term: Hyperchloremia
    term:
      id: HP:0011423
      label: Hyperchloremia
  evidence:
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare genetic form of hypertension characterized by hyperkalemia, mild hyperchloremic metabolic acidosis, normal or elevated aldosterone, low renin, with normal renal glomerular filtration rate (GFR)."
    explanation: Orphanet's definition names hyperchloremic acidosis in the syndrome.
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels."
    explanation: GeneReviews lists hyperchloremia among the associated findings.
- category: Metabolic/Laboratory
  name: Suppressed plasma renin
  description: >-
    Low renin distinguishes this syndrome from the salt-wasting
    pseudohypoaldosteronism type 1 disorders, in which renin and aldosterone are
    both high.
  phenotype_term:
    preferred_term: Decreased circulating renin concentration
    term:
      id: HP:0003351
      label: Decreased circulating renin concentration
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "With hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels; AND/OR"
    explanation: Suppressed plasma renin is one of the GeneReviews clinical diagnostic criteria.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although this trial improved biochemical markers, it was discontinued once suppressed renin and aldosterone levels pointed toward PHA2."
    explanation: Suppressed renin and aldosterone redirected the diagnosis in this PHA2D patient.
- category: Metabolic/Laboratory
  name: Aldosterone inappropriately low for the degree of hyperkalemia
  description: >-
    The feature the disease is named for, and a differential-diagnosis
    discriminator against the salt-wasting pseudohypoaldosteronism type 1
    disorders and against aldosterone deficiency, where renin and aldosterone
    move together. Hyperkalemia is normally a potent stimulus to aldosterone
    secretion, so a level that is merely unremarkable is already inappropriate
    here.

    The binding is deliberately the umbrella HPO term rather than
    `HP:0004319` Decreased circulating aldosterone concentration, because the
    sources disagree on the absolute direction and HPO has no term for a level
    inappropriate to its own stimulus. GeneReviews calls aldosterone variable
    but relatively low for the potassium; Orphanet's definition says normal or
    elevated; the two reported pseudohypoaldosteronism type 2 cases cited here
    both describe it as suppressed alongside renin. Binding a directional term
    would assert one of those readings over the others, so the specificity is
    carried in `preferred_term` and in this description instead.
  phenotype_term:
    preferred_term: Aldosterone inappropriately low for the degree of hyperkalemia
    term:
      id: HP:0040085
      label: Abnormal circulating aldosterone concentration
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion)."
    explanation: The GeneReviews statement of the paradox, and the wording this row's name follows.
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "normal or elevated aldosterone, low renin"
    explanation: Orphanet's wording, which differs from GeneReviews on the absolute direction and is the reason the umbrella term is bound.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it was discontinued once suppressed renin and aldosterone levels pointed toward PHA2"
    explanation: In this PHA2D patient aldosterone was frankly suppressed, not merely relatively low.
- category: Renal
  name: Hypercalciuria
  description: >-
    Documented in KLHL3-mutant families, where urinary calcium excretion in
    affected members was about 0.61 against 0.24 mmol calcium per mmol
    creatinine in unaffected relatives. It is milder than the hypercalciuria of
    the WNK4 Q565E form. The mechanism in the KLHL3 form has not been
    established, which is why no causal edge is drawn to this node; see the
    knowledge gap recorded under `discussions`.
  phenotype_term:
    preferred_term: Hypercalciuria
    term:
      id: HP:0002150
      label: Hypercalciuria
  evidence:
  - reference: PMID:25925082
    reference_title: "Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FHHt caused by KLHL3 mutations is accompanied by hypercalciuria as well as hyperkalemia and hypertension."
    explanation: Establishes hypercalciuria specifically in KLHL3-mutant familial hyperkalemic hypertension.
  - reference: PMID:25925082
    reference_title: "Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "UCa levels in affected subjects in the two families were significantly higher than in unaffected subjects (0.608 ± 0.196 vs. 0.236 ± 0.053 mmol Ca per mmol creatinine, respectively (p < 0.0001))."
    explanation: Quantifies the urinary calcium excretion difference in two KLHL3 families.
- category: Musculoskeletal
  name: Muscle weakness
  frequency: OCCASIONAL
  description: >-
    Attributable to the hyperkalemia. A child with biallelic KLHL3 disease
    presented with muscle aches and fatigue rather than with hypertension.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001324 | Muscle weakness | Occasional (29-5%)"
    explanation: Orphanet records muscle weakness as occasional in pseudohypoaldosteronism type 2.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a nine-year-old boy presenting with chronic fatigue, muscle aches, and growth failure."
    explanation: Muscle symptoms were a presenting complaint in a patient with PHA2D.
- category: Musculoskeletal
  name: Periodic paralysis
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Periodic paralysis
    term:
      id: HP:0003768
      label: Periodic paralysis
  evidence:
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003768 | Periodic paralysis | Occasional (29-5%)"
    explanation: Orphanet records periodic paralysis as occasional in pseudohypoaldosteronism type 2.
- category: Growth
  name: Short stature
  frequency: OCCASIONAL
  description: >-
    Short stature was the presenting feature of one of the two KLHL3 families in
    which hypercalciuria was studied.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004322 | Short stature | Occasional (29-5%)"
    explanation: Orphanet records short stature as occasional in pseudohypoaldosteronism type 2.
  - reference: PMID:25925082
    reference_title: "Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presenting features were short stature in the first family, and transient tachypnea of the newborn (TTN) in the second."
    explanation: Short stature was the presenting feature in a KLHL3-mutant family.
- category: Growth
  name: Growth delay
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001510 | Growth delay | Occasional (29-5%)"
    explanation: Orphanet records growth delay as occasional in pseudohypoaldosteronism type 2.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a nine-year-old boy presenting with chronic fatigue, muscle aches, and growth failure."
    explanation: Growth failure was a presenting feature in a patient with PHA2D.
- category: Gastrointestinal
  name: Nausea and vomiting
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nausea and vomiting
    term:
      id: HP:0002017
      label: Nausea and vomiting
  evidence:
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002017 | Nausea and vomiting | Frequent (79-30%)"
    explanation: Orphanet records nausea and vomiting as frequent in pseudohypoaldosteronism type 2.
- category: Head and Neck
  name: Abnormal dental enamel morphology
  frequency: OCCASIONAL
  description: >-
    Recorded by Orphanet for the syndrome as a whole. No KLHL3-specific report of
    a dental phenotype was identified, so this row is not stratified to the KLHL3
    form.
  phenotype_term:
    preferred_term: Abnormal dental enamel morphology
    term:
      id: HP:0000682
      label: Abnormal dental enamel morphology
  evidence:
  - reference: ORPHA:757
    reference_title: "Pseudohypoaldosteronism type 2"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000682 | Abnormality of dental enamel | Occasional (29-5%)"
    explanation: Orphanet records a dental enamel abnormality as occasional in pseudohypoaldosteronism type 2.
- category: Constitutional
  name: Fatigue
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a nine-year-old boy presenting with chronic fatigue, muscle aches, and growth failure."
    explanation: Chronic fatigue was the leading presenting symptom in a patient with PHA2D.
diagnosis:
- name: Biochemical and hormonal profile
  description: >-
    Hyperkalemia with a normal glomerular filtration rate, hyperchloremia,
    metabolic acidosis and suppressed plasma renin, with an aldosterone that is
    low relative to the potassium level, establishes the clinical diagnosis.
    Hypertension supports it but is not required.
  measurements:
  - preferred_term: potassium, serum or plasma
    term:
      id: LOINC:2823-3
      label: Potassium [Moles/volume] in Serum or Plasma
  - preferred_term: chloride, serum or plasma
    term:
      id: LOINC:2075-0
      label: Chloride [Moles/volume] in Serum or Plasma
  - preferred_term: bicarbonate, serum or plasma
    term:
      id: LOINC:1963-8
      label: Bicarbonate [Moles/volume] in Serum or Plasma
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "With hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels; AND/OR"
    explanation: The GeneReviews clinical diagnostic criteria for pseudohypoaldosteronism type II.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although this trial improved biochemical markers, it was discontinued once suppressed renin and aldosterone levels pointed toward PHA2."
    explanation: The hormonal profile redirected this case from mineralocorticoid deficiency to pseudohypoaldosteronism type 2.
- name: Molecular genetic testing of the familial hyperkalemic hypertension genes
  description: >-
    Sequencing of KLHL3, CUL3, WNK1 and WNK4 assigns the subtype. KLHL3 is the
    only one of the four in which a biallelic result is diagnostic as well as a
    heterozygous one, so zygosity has to be reported and interpreted rather than
    the variant alone.
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "By the identification of a heterozygous pathogenic variant in CUL3, WNK1, or WNK4 or a heterozygous pathogenic variant or biallelic pathogenic variants in KLHL3."
    explanation: States the molecular diagnostic criterion, and that KLHL3 admits both zygosities.
  - 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: "three with PHAII (heterozygous KLHL3 or CUL3 mutations) exhibiting hyperkalemia and acidosis that were responsive to thiazides"
    explanation: Genetic testing assigned the subtype in a mixed pseudohypoaldosteronism series including KLHL3 patients.
- name: Urinary exosomal NCC abundance
  description: >-
    A research measurement rather than a clinical test. Urinary exosomal NCC is
    raised in affected KLHL3 carriers, which demonstrates the mechanism in
    patients rather than only in models. Heterozygous relatives in a recessive
    family also showed a rise without a clinical phenotype, so the measurement
    does not separate carriers from patients.
  evidence:
  - reference: PMID:28511177
    reference_title: "Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased urinary NCC was found in affected members (heterozygous) with dominant KLHL3 Q309R, and in affected members (homozygous) of the recessive form."
    explanation: Urinary cotransporter abundance is raised in affected carriers of both dominant and recessive KLHL3 genotypes.
  - reference: PMID:28511177
    reference_title: "Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unexpectedly, in the recessive disease, heterozygotes seemed to have increased urinary NCC as well, apparently not sufficient quantitatively to produce a clinical phenotype."
    explanation: Unaffected heterozygotes also showed raised urinary cotransporter abundance, limiting the measurement's diagnostic value.
treatments:
- name: Thiazide diuretic therapy
  description: >-
    Thiazides inhibit NCC, the transporter the disease makes overactive, so this
    is mechanism-directed therapy rather than symptomatic treatment, and it
    corrects the hyperkalemia, the acidosis and the hypertension together.
    Dosing needs individual titration: a normotensive child given 0.5 mg/kg/day
    of hydrochlorothiazide developed symptomatic hypotension and was stabilised
    on 0.25 mg/kg on alternate days. Chronic use carries class side effects and
    provokes compensatory adaptation in the nephron, which is what motivates
    work on direct inhibitors of the cascade upstream.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydrochlorothiazide
      term:
        id: CHEBI:5778
        label: hydrochlorothiazide
  target_mechanisms:
  - target: NCC Hyperphosphorylation in the Distal Convoluted Tubule
    description: >-
      Thiazides block the sodium chloride cotransporter that the WNK, SPAK and
      OSR1 cascade has activated, acting on the proximate cause of the salt
      retention.
    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: "virtually all patients with KLHL3 and CUL3 mutations have been treated with thiazide diuretics, inhibitors of the Na-Cl cotransporter NCC, with correction of phenotypic abnormalities"
      explanation: Names the cotransporter as the thiazide target and reports correction of the phenotype in KLHL3 patients.
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Electrolyte and blood pressure abnormalities of PHAII in children and adults are often corrected with thiazide diuretics."
    explanation: GeneReviews states the first-line treatment and what it corrects.
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The dosage was ultimately titrated to an alternate-day, low-dose regimen (0.25 mg/kg), which successfully maintained metabolic stability while minimizing adverse effects."
    explanation: Records the reduced, alternate-day regimen needed in a normotensive PHA2D patient.
  - 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: Thiazide diuretics were the treatment used for the KLHL3 and CUL3 patients in this series.
  - reference: PMID:32724175
    reference_title: "WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Thiazide diuretics are currently the main treatment option for Gordon's syndrome. However, they have a number of side effects, and chronic usage can lead to compensatory adaptations in the nephron that counteract their action."
    explanation: Records the limitations of chronic thiazide therapy that motivate work on upstream inhibitors.
- name: Dietary sodium and potassium restriction
  description: >-
    Because the disease is salt dependent, restricting dietary salt treats the
    hypertension and restricting potassium treats the hyperkalemia. GeneReviews
    frames the converse as a circumstance to avoid: untreated patients should not
    take excessive salt or potassium.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Increased Distal Nephron Sodium Chloride Reabsorption
    description: >-
      Reducing the sodium chloride load limits what the overactive cotransporter
      can retain.
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Untreated individuals with PHAII should avoid excessive intake of foods high in salt and potassium as these may exacerbate hypertension and hyperkalemia."
    explanation: GeneReviews names salt and potassium excess as circumstances to avoid.
  - 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: "is a salt-dependent form of hypertension caused by mutations in the regulators of the thiazide-sensitive Na+-Cl- co-transporter NCC ... and is effectively treated by thiazide diuretics and/or dietary salt restriction"
    explanation: States that dietary salt restriction is effective treatment; quoted from this paper's framing of the disease rather than from its own genetic results.
- name: Blood pressure and electrolyte surveillance
  description: >-
    Routine electrolyte and blood pressure measurement, with blood pressure
    control pursued for its own sake because of the cardiovascular, renal and
    cerebrovascular risk the hypertension carries. Pregnancy needs separate
    handling, since thiazides have been associated with adverse fetal outcome,
    particularly in the first trimester.
  action_category: MONITORING
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Control of blood pressure is important to reduce the risk of cardiovascular and renal disease and stroke."
    explanation: GeneReviews states the rationale for blood pressure control beyond electrolyte correction.
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Some antihypertensive medications, including thiazide diuretics, have been associated with adverse fetal outcome, especially when taken during the first trimester of pregnancy; referral to an obstetrics group with expertise in high-risk pregnancies should be considered."
    explanation: Records the pregnancy caveat on the first-line drug.
- name: Testing of at-risk relatives
  description: >-
    Serum potassium and blood pressure measurement, or targeted testing for the
    familial variant, identifies affected relatives before complications
    develop. Zygosity governs who is at risk: in a recessive kindred
    heterozygous relatives are unaffected, while in a dominant kindred they are
    not.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:22073419
    reference_title: "Pseudohypoaldosteronism Type II."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Measurement of serum potassium concentration and blood pressure or identification of the known familial CUL3, KLHL3, WNK1, and WNK4 pathogenic variant(s) in first-degree relatives of individuals with PHAII allows for early diagnosis and treatment"
    explanation: GeneReviews states the evaluation of relatives at risk.
  - 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: "In these kindreds, affected members are confined to siblings of index cases who inherited the same two mutations, while unaffected relatives inherited zero or one mutation"
    explanation: In recessive kindreds only biallelic relatives are affected, which determines who needs follow-up.
animal_models:
- name: KLHL3 R528H knock-in mouse
  species: Mouse
  genotype: Klhl3 R528H/+ (heterozygous knock-in)
  publication: PMID:24821705
  description: >-
    A heterozygous knock-in of the recurrent dominant human Kelch-domain allele.
    It reproduces salt-sensitive hypertension, hyperkalemia and metabolic
    acidosis with raised renal WNK1, WNK4 and phosphorylated NCC, so it models
    the dominant form of the human disease at the level of both mechanism and
    phenotype.
  modeled_mechanisms:
  - target: WNK1 and WNK4 Kinase Accumulation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >-
      Both WNK substrates accumulate in the kidney of the heterozygous knock-in,
      and the mutant protein binds neither.
    readouts:
    - name: Renal WNK1 and WNK4 protein abundance
      target: WNK1 and WNK4 Kinase Accumulation
      direction: INCREASED
      interpretation: Direct measurement of the accumulation this node asserts.
      evidence:
      - reference: PMID:24821705
        reference_title: "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Interestingly, the protein expression of both WNK1 and WNK4 was significantly increased in the KLHL3(R528H/+) mouse kidney, confirming that increases in these WNK kinases activated the WNK-OSR1/SPAK-NCC phosphorylation cascade in KLHL3(R528H/+) knock-in mice."
        explanation: Reports the raised renal WNK1 and WNK4 protein levels.
    evidence:
    - reference: PMID:24821705
      reference_title: "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, we found that increased protein expression levels of WNK1 and WNK4 kinases cause PHAII by KLHL3 R528H mutation due to impaired KLHL3-Cullin3-mediated ubiquitination."
      explanation: The authors attribute the model's phenotype to the WNK accumulation this node names.
  - target: NCC Hyperphosphorylation in the Distal Convoluted Tubule
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Renal cotransporter phosphorylation is increased, with the salt-sensitive
      hypertension, hyperkalemia and acidosis that follow from it.
    readouts:
    - name: Renal phosphorylated NCC abundance
      target: NCC Hyperphosphorylation in the Distal Convoluted Tubule
      direction: INCREASED
      interpretation: The phosphorylation state this node asserts, measured in the model kidney.
      evidence:
      - reference: PMID:24821705
        reference_title: "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Moreover, the phosphorylation of NCC was increased in the KLHL3(R528H/+) mouse kidney, indicating that the KLHL3(R528H/+) knock-in mouse is an ideal mouse model of PHAII."
        explanation: Reports increased renal cotransporter phosphorylation in the knock-in.
    limitations: >-
      The hypertension in the model is salt sensitive, that is, it needs a salt
      load to appear, whereas human carriers are hypertensive on an ordinary
      diet. One allele is modelled, so the recessive form and the
      allele-specific behaviour of S410L and the serine 433 substitutions are
      outside its scope.
    evidence:
    - reference: PMID:24821705
      reference_title: "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "KLHL3(R528H/+) knock-in mice exhibited salt-sensitive hypertension, hyperkalemia and metabolic acidosis."
      explanation: The model reproduces the three cardinal features of the human disease.
- name: KLHL3 knockout mouse
  species: Mouse
  genotype: Klhl3-/- and Klhl3+/- (beta-galactosidase reporter knockout)
  publication: PMID:28052936
  description: >-
    A null allele carrying a beta-galactosidase reporter, which separates the
    two human inheritance modes experimentally. Homozygous nulls have the
    pseudohypoaldosteronism type II phenotype with raised renal WNK1 and WNK4;
    heterozygous nulls have neither. That asymmetry is the evidence that the
    dominant human alleles are dominant negative rather than haploinsufficient,
    and the reporter also shows where KLHL3 is expressed outside the kidney
    without WNK accumulating there.
  modeled_mechanisms:
  - target: Loss of KLHL3 Substrate Adaptor Function
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Complete loss of the adaptor produces the disease phenotype, and the
      review literature reads the homozygous null as the closest available model
      of the recessive human form.
    limitations: >-
      A null allele is not a missense allele: it cannot reproduce the
      dominant-negative heterodimer poisoning the human dominant alleles act
      through, which is precisely why the heterozygote is unaffected. No mouse
      carrying a recessive human missense allele has been reported.
    evidence:
    - reference: PMID:28052936
      reference_title: "KLHL3 Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "KLHL3-/- mice also showed PHAII-like phenotypes, whereas KLHL3+/- mice did not."
      explanation: Complete adaptor loss gives the disease phenotype while a single null allele does not.
    - reference: PMID:39699086
      reference_title: "Familial Hyperkalemic Hypertension."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "the phenotype of constitutive global KLHL3−/− mice generated by the Uchida group(151) likely recapitulates the majority of recessive mutations"
      explanation: The review reads the homozygous null as standing in for the recessive human genotypes.
  - target: Dominant-Negative Poisoning of KLHL3 Dimers
    relationship: FAILS_TO_RECAPITULATE
    fidelity: UNKNOWN
    model_scale: ORGANISM
    description: >-
      The heterozygous null does not develop the disease, so this model does not
      reproduce the dominant human phenotype. That negative result is the
      argument for the dominant-negative mechanism rather than a shortcoming of
      the experiment.
    limitations: >-
      A deletion removes the subunit instead of substituting it, so there is no
      mutant protein available to poison a dimer. The model therefore bounds the
      mechanism from one side only and cannot demonstrate the poisoning
      directly.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The model's quantity is KLHL3 gene dose, halved by deletion. The node's
        quantity is the proportion of KLHL3 dimers carrying a mutant subunit,
        which a heterozygous missense allele raises while leaving gene dose
        intact. The two differ in the direction that matters here.
    evidence:
    - reference: PMID:28052936
      reference_title: "KLHL3 Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This clearly demonstrates that the heterozygous deletion of KLHL3 was not sufficient to cause PHAII, indicating that autosomal dominant type PHAII is caused by the dominant negative effect of mutant KLHL3."
      explanation: The heterozygous null's lack of phenotype is what establishes the dominant-negative reading.
differential_diagnoses:
- name: Pseudohypoaldosteronism type 2E
  disease_term:
    preferred_term: pseudohypoaldosteronism type 2E
    term:
      id: MONDO:0013782
      label: pseudohypoaldosteronism type 2E
  description: >-
    The CUL3 form, biochemically identical but the most severe of the four. It
    presents far earlier, with deeper hyperkalemia and acidosis, and its variants
    are dominant and largely de novo rather than inherited.
  distinguishing_features:
  - Much younger age at presentation, and 94 percent hypertensive by age 18 against 17 percent for dominant KLHL3
  - Dominant and predominantly de novo CUL3 variants, so often no family history
  - No recessive form, where KLHL3 has one
  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: Contrasts the inheritance of the KLHL3 and CUL3 forms.
  - 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: "| CUL3 | 17 | 21 | 9 ±6 | 7.5 ±0.9 | 15.5 ±2.0 | 94 |"
    explanation: The CUL3 row of the genotype-stratified table, with a mean diagnosis age of 9 years and 94 percent hypertensive by age 18.
  - 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: "Pathogenic variants in WNK1, WNK4, KLHL3, and CUL3 have been identified, with CUL3 mutations particularly associated with early-onset and severe phenotypes."
    explanation: Confirms the early-onset, severe character of the CUL3 form relative to the others.
- name: Pseudohypoaldosteronism type 2B
  description: >-
    The WNK4 form. It shares the mechanism from the WNK accumulation step
    onwards, since its missense alleles block the same KLHL3 interaction from the
    substrate side, but it is milder than the KLHL3 form and has only a dominant
    mode. Its hypercalciuria is more marked.
  distinguishing_features:
  - Milder hyperkalemia and acidosis than the KLHL3 form
  - Dominant inheritance only
  - More severe hypercalciuria than in KLHL3 disease
  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: "Among the other mutant loci, there remain significant differences in disease severity (rank order recessive KLHL3 > dominant KLHL3 > WNK4 > WNK1)."
    explanation: Places the WNK4 form below both KLHL3 forms in severity.
  - reference: PMID:25925082
    reference_title: "Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypercalciuria in FHHt with KLHL3 mutations is less severe than that observed in FHHt with the Q565E WNK4 mutation"
    explanation: Quantifies the difference in hypercalciuria between the KLHL3 and WNK4 forms.
  - reference: PMID:37285722
    reference_title: "Identification of a novel KLHL3-interacting motif in the C-terminal region of WNK4."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This may be one of the reasons why PHAII is less severe when WNK4 is mutated compared to KLHL3 is mutated."
    explanation: Offers a molecular reason, a second KLHL3-binding motif in WNK4, for the milder WNK4 phenotype.
- name: Pseudohypoaldosteronism type 2A
  description: >-
    The WNK1 form, the mildest of the four, with the latest mean age at
    diagnosis and the least deranged potassium and bicarbonate.
  distinguishing_features:
  - Mildest biochemistry of the four genes and the latest presentation
  - Attributed to raised kidney-specific WNK1 rather than a coding change in an adaptor
  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: "| WNK1 | 2 | 23 | 36 ±20 | 5.8 ±0.8 | 22.4 ±4.6 | 13 |"
    explanation: The WNK1 row of the genotype-stratified table, with a mean potassium of 5.8 and bicarbonate of 22.4 mmol/L.
  - reference: PMID:35894282
    reference_title: "WNK1 in the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The high sensitivity of KS-WNK1 to KLHL3-targeted degradation and the low levels of L-WNK1 in the DCT, led to propose that this type of FHHt is mainly due to increased KS-WNK1 protein in the DCT."
    explanation: The WNK1 form is attributed to raised kidney-specific WNK1, the isoform most sensitive to KLHL3-directed degradation.
- name: Calcineurin inhibitor nephrotoxicity
  description: >-
    Tacrolimus and ciclosporin produce an acquired phenocopy. Calcineurin is the
    phosphatase that removes the KLHL3 serine 433 phosphate, so inhibiting it
    locks the adaptor in its non-binding state and reproduces the whole cascade.
    Hypertension and hyperkalemia are common adverse effects of these drugs for
    this reason.
  distinguishing_features:
  - Temporal relation to starting a calcineurin inhibitor, and no family history
  - Reversible on withdrawal or dose reduction, where the genetic disease is not
  evidence:
  - reference: PMID:30718414
    reference_title: "Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)-CUL3 ubiquitin ligase complex."
    explanation: States that calcineurin inhibitors mimic the genetic disease, which this paper then traces to the shared serine 433 node.
  - reference: PMID:30718414
    reference_title: "Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, tacrolimus attenuates KLHL3-mediated WNK4 ubiquitylation and degradation, while this effect is absent in KLHL3 with S433A substitution."
    explanation: The drug effect requires serine 433, the residue the S433G and S433N disease alleles occupy.
- name: Hyperkalemic renal tubular acidosis from aldosterone deficiency or resistance
  description: >-
    Hyperkalemic distal renal tubular acidosis from true hypoaldosteronism or
    from mineralocorticoid resistance gives a similar potassium and acid-base
    picture. Renin and aldosterone separate them: both are raised in the
    salt-wasting pseudohypoaldosteronism type 1 disorders and in aldosterone
    deficiency, and both are suppressed here. A response to fludrocortisone can
    mislead, since it improved the biochemistry of a PHA2D patient being treated
    for presumed mineralocorticoid deficiency.
  distinguishing_features:
  - Suppressed renin and aldosterone, where salt-wasting and aldosterone-deficient states have both raised
  - Volume expansion with hypertension, rather than salt wasting with hypovolemia and hyponatremia
  - Sustained correction by a thiazide, which addresses the overactive cotransporter
  evidence:
  - reference: PMID:42057493
    reference_title: "Challenges in the Diagnosis and Management of a Paediatric Patient With Normotensive Pseudohypoaldosteronism Type IID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to an initial clinical suspicion of isolated mineralocorticoid deficiency, a diagnostic trial of fludrocortisone was initiated while awaiting definitive results."
    explanation: Mineralocorticoid deficiency was the initial working diagnosis in a patient with PHA2D.
  - 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: "Pseudohypoaldosteronism (PHA) is a rare disorder characterized by renal resistance to mineralocorticoids, leading to hyperkalemia, hyponatremia, and metabolic acidosis."
    explanation: The pseudohypoaldosteronism type 1 disorders share the hyperkalemia and acidosis but add the hyponatremia of salt wasting.
  - 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."
    explanation: Records that aldosterone pathway defects and pseudohypoaldosteronism type 2 are confused on first assessment.
- name: Gordon syndrome (distal arthrogryposis type 3)
  description: >-
    A name collision rather than a clinical differential. The eponym Gordon
    syndrome is used both for this renal syndrome and for distal arthrogryposis
    type 3, a musculoskeletal disorder with joint contractures and cleft palate
    that is curated separately in this knowledge base as
    `kb/disorders/Gordon_Syndrome.yaml`. The two share no mechanism and no
    overlapping presentation; the hazard is a literature or ontology search
    returning one for the other.
  distinguishing_features:
  - Congenital joint contractures and cleft palate, with no electrolyte abnormality
  - Not caused by any of the four familial hyperkalemic hypertension genes
  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"
    explanation: Documents that the renal syndrome carries the Gordon eponym, which is the source of the collision; quoted from the paper's framing rather than its results.
discussions:
- discussion_id: acidosis_mechanism_in_klhl3_disease
  kind: KNOWLEDGE_GAP
  prompt: >-
    What mechanism produces the metabolic acidosis in KLHL3-related
    pseudohypoaldosteronism type 2, and is it the same mechanism as in the WNK4
    form?
  attaches_to:
  - pathophysiology#Hyperkalemia-Driven Impairment of Renal Ammonium Excretion
  rationale: >-
    Two incompatible accounts exist and neither was obtained in a KLHL3
    genotype. The constitutively active SPAK mouse, which isolates cotransporter
    hyperactivation, makes the acidosis secondary to hyperkalemia through
    proximal tubule ammonia generation and collecting duct ammonia transport,
    and that is the chain this entry encodes. The WNK4 Q562E mouse instead
    attributes it to excessive collecting duct bicarbonate secretion through
    pendrin, with normal proton secretion and ammonium excretion. A cohort of 18
    human WNK4 Q565E patients had renal ammonium excretion no lower than
    unaffected subjects, which fits neither mouse cleanly. Whether the KLHL3 form
    follows either account is untested.
  proposed_experiments:
  - experiment_id: klhl3_acid_base_ammonia_handling
    experiment_design: TARGETED_PERTURBATION
    name: Acid-base and ammonia handling in KLHL3 R528H knock-in and KLHL3 null mice
    description: >-
      Measure urinary ammonium excretion, urine pH under an acid load, proximal
      tubule ammoniagenic enzyme expression and collecting duct Rhcg abundance in
      Klhl3 R528H/+ and Klhl3 null mice, before and after thiazide correction of
      the hyperkalemia, and test whether pendrin deletion corrects the acidosis
      as it does in the WNK4 model.
    would_support:
    - pathophysiology#Hyperkalemia-Driven Impairment of Renal Ammonium Excretion
    supporting_outcome:
    - Reduced urinary ammonium excretion with reduced proximal ammoniagenic enzyme expression that normalises when a thiazide corrects the potassium
    - No correction of the acidosis by pendrin deletion in a KLHL3 genotype
    refuting_outcome:
    - Normal ammonium excretion with correction of the acidosis by pendrin deletion, which would place the KLHL3 form with the WNK4 bicarbonate secretion account instead
    readouts:
    - name: Urinary ammonium excretion
      target: pathophysiology#Hyperkalemia-Driven Impairment of Renal Ammonium Excretion
      direction: DECREASED
      interpretation: >-
        The quantity the encoded mechanism predicts will fall, and the one the
        human WNK4 cohort did not show falling.
- discussion_id: hypercalciuria_mechanism_in_klhl3_disease
  kind: KNOWLEDGE_GAP
  prompt: >-
    By what mechanism does hypercalciuria arise in KLHL3-related
    pseudohypoaldosteronism type 2?
  attaches_to:
  - phenotypes#Hypercalciuria
  rationale: >-
    Hypercalciuria is established as a feature of KLHL3-mutant families and is
    milder than in the WNK4 Q565E form, but the only mechanistic work is in the
    WNK4 D561A mouse, where reduced paracellular calcium reabsorption in the
    thick ascending limb was implicated and TRPV6 and calbindin rose as an
    apparent compensation. Nothing of the kind has been measured in a KLHL3
    genotype, and the milder human phenotype suggests the two may not share a
    mechanism. The phenotype is therefore left unconnected in the pathograph
    rather than attached to the cotransporter node by inference.
  proposed_experiments:
  - experiment_id: klhl3_renal_calcium_handling
    experiment_design: TARGETED_PERTURBATION
    name: Renal calcium handling in KLHL3 R528H knock-in mice
    description: >-
      Measure urinary calcium excretion, the furosemide-induced calciuric
      response as a probe of thick ascending limb paracellular transport, and
      TRPV5, TRPV6 and calbindin abundance in Klhl3 R528H/+ mice, for direct
      comparison with the published WNK4 D561A data.
    would_support:
    - phenotypes#Hypercalciuria
    supporting_outcome:
    - Raised urinary calcium with a blunted furosemide calciuric response, matching the thick ascending limb account from the WNK4 model
    refuting_outcome:
    - Raised urinary calcium with a normal furosemide response, which would place the defect distally and separate the KLHL3 mechanism from the WNK4 one
- discussion_id: recessive_missense_versus_null
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does a recessive KLHL3 missense allele behave like a null allele in vivo?
  attaches_to:
  - pathophysiology#Loss of KLHL3 Substrate Adaptor Function
  - genetic#KLHL3
  rationale: >-
    The recessive human genotypes include missense alleles such as S410L, which
    destabilises the protein as well as weakening WNK4 binding, and S553L, whose
    biochemistry has not been characterised. The only in vivo model of the
    recessive form is a complete gene deletion, which the review literature
    takes as standing in for the recessive alleles. That substitution is
    untested, and it matters for the severity ranking: recessive KLHL3 disease is
    the most severe of the four genes after CUL3, which a pure null would be
    expected to explain but a partially functional missense allele would not.
  proposed_experiments:
  - experiment_id: recessive_klhl3_missense_knockins
    experiment_design: TARGETED_PERTURBATION
    name: Knock-in mice carrying recessive human KLHL3 missense alleles
    description: >-
      Generate homozygous Klhl3 S410L and S553L knock-in mice and compare renal
      WNK1, WNK4, phosphorylated SPAK and phosphorylated NCC abundance, blood
      pressure and electrolytes against Klhl3 null and wild-type littermates.
    would_support:
    - pathophysiology#Loss of KLHL3 Substrate Adaptor Function
    supporting_outcome:
    - Homozygous missense knock-ins phenocopy the null for WNK accumulation and electrolytes, which would justify using the null as a model of recessive disease
    refuting_outcome:
    - A milder or qualitatively different phenotype in the missense knock-ins, which would mean the published recessive model overstates the genotype it stands for
- discussion_id: upstream_cascade_inhibitors
  kind: OPEN_QUESTION
  prompt: >-
    Would a direct WNK or SPAK/OSR1 inhibitor treat this disease better than a
    thiazide?
  attaches_to:
  - pathophysiology#SPAK and OSR1 Hyperactivation
  - treatments#Thiazide diuretic therapy
  rationale: >-
    Thiazides work and are the standard of care, but chronic use carries class
    side effects and provokes compensatory nephron adaptation that offsets the
    drug. The epistasis experiments make an unusually specific prediction about
    the alternative: in the WNK4 D561A mouse, removing SPAK alone abolished the
    phenotype while removing OSR1 in the kidney tubule did not, so a
    SPAK-selective inhibitor would be expected to work and an OSR1-selective one
    would not. Molecular inhibitors of the pathway are under development, but
    none has been tested in a KLHL3 genotype or in patients with this disease.
  proposed_experiments:
  - experiment_id: spak_inhibitor_in_klhl3_knockin
    experiment_design: TARGETED_PERTURBATION
    name: SPAK-selective inhibition in KLHL3 R528H knock-in mice
    description: >-
      Give a SPAK-selective inhibitor and, in parallel, a thiazide to Klhl3
      R528H/+ mice on a normal and a high-salt diet, and compare blood pressure,
      serum potassium and bicarbonate, phosphorylated NCC abundance, and the
      compensatory nephron remodelling that chronic thiazide treatment induces.
    would_support:
    - pathophysiology#SPAK and OSR1 Hyperactivation
    supporting_outcome:
    - Correction of blood pressure, potassium and bicarbonate at least equal to the thiazide arm, with lower phosphorylated NCC and without the compensatory remodelling the thiazide arm shows
    refuting_outcome:
    - No improvement in the electrolyte or blood pressure abnormalities, which would mean SPAK inhibition does not reach the cascade in a KLHL3 genotype even though Spak deletion rescues the WNK4 one
references:
- reference: PMID:22073419
  title: "Pseudohypoaldosteronism Type II."
  tags:
  - GeneReviews

📚

References & Deep Research

References

1

PMID:22073419

Pseudohypoaldosteronism Type II.

No top-level findings curated for this source.

Deep Research

1

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.

Evaluations and curation notes (2)

Record notes

Scope of the syndrome-level sources. The Orphanet record cited throughout (ORPHA:757, pseudohypoaldosteronism type 2) and the GeneReviews chapter (PMID:22073419) both describe pseudohypoaldosteronism type II across all four causative genes (WNK1, WNK4, KLHL3, CUL3) rather than the KLHL3 form alone, so their phenotype frequencies and their statement that prevalence is unknown apply to the syndrome as a whole. Figures specific to KLHL3 come from the Boyden cohort (PMID:22266938), whose genotype-stratified table reports its 8 recessive and 16 dominant KLHL3 kindreds as separate rows. Name collision. `kb/disorders/Gordon_Syndrome.yaml` in this knowledge base is distal arthrogryposis type 3, an unrelated musculoskeletal disorder sharing the eponym. It is not a parent or a relative of this entry and appears under `differential_diagnoses` only to record the collision; the renal sense of Gordon syndrome is this disease and its sibling gene forms. Sibling gene forms. PHA2A (WNK1), PHA2B (WNK4) and PHA2E (CUL3) are separate MONDO concepts sharing this mechanism from the WNK accumulation step onwards. They are cited here as differential diagnoses; their pathophysiology is not duplicated in this entry. Several cited experiments were done in WNK4 D561A or constitutively active SPAK mice rather than in a KLHL3 genotype. They are used only where the claim is about the shared cascade downstream of WNK accumulation, which the KLHL3 R528H knock-in independently shows is engaged, and each explanation says which genotype the result came from. No KLHL3-specific claim rests on them. Mechanism of the acidosis. No study has established it in a KLHL3 genotype. The constitutively active SPAK mouse, which isolates cotransporter hyperactivation, attributes it to a secondary effect of hyperkalemia on proximal tubule and collecting duct ammonia handling, and that is the chain encoded here. The WNK4 Q562E mouse supports a different account, excessive collecting duct bicarbonate secretion through pendrin, and a cohort of 18 human WNK4 Q565E patients had renal ammonium excretion no lower than unaffected subjects. The disagreement is recorded as a knowledge gap rather than resolved in the pathograph. Muscle weakness, periodic paralysis, fatigue and nausea with vomiting are recorded as phenotypes but left unwired to the pathograph. The aldosterone row is unwired for the same reason: the cited sources state the paradox but none states what produces it, and the obvious reading, that volume expansion removes the angiotensin II drive while the potassium stimulus persists, is an inference no quoted source makes. They are clinically attributed to the hyperkalemia, and the entry's description says so, but no source found states that causal link for this syndrome: Orphanet lists the features without a mechanism, GeneReviews does not mention them, and the one PHA2D case report gives them as presenting complaints rather than as consequences of a measured potassium. A `sequelae` edge from Hyperkalemia would be the right encoding once such a source exists. The same holds for short stature and growth delay, where the only candidate source (PMID:41380172) reports normal growth in its own patient. GeneReviews describes hypercalciuria in four words, below the snippet-length floor, so that claim is cited from PMID:25925082 instead, which is also KLHL3-specific and quantitative. GeneReviews remains the entry's phenotype baseline and is tagged in `references`. Hypercalciuria is documented in KLHL3-mutant families (PMID:25925082) but is deliberately left unwired to the pathograph. The only mechanistic account in the literature comes from the WNK4 D561A mouse, a different genotype whose human counterpart has more severe hypercalciuria, so no causal edge from the cotransporter node is sourced for the KLHL3 form. No ClinGen gene-disease validity assertion exists for the KLHL3 and pseudohypoaldosteronism type 2D pair in the committed ClinGen export (`kb/genes/ingest/clingen_gene_validity.tsv` and `cache/clingen/gene_validity.csv` carry one for CUL3 with PHA2E only), so no `gene_disease_validity` record is copied into this entry. Three leads from the openscientist deep-research report were checked and not used. It gives KLHL3 as HGNC:15531, which is EBNA1BP2; the correct identifier, read from the HGNC REST record for the symbol, is hgnc:6354. It binds suppressed renin to HP:0040331, which HPO calls Focal hypointensity of cerebral white matter on MRI, and hyperchloremic metabolic acidosis to HP:0004910, which is Bicarbonate-wasting renal tubular acidosis; the terms used here (HP:0003351, HP:0004918) were resolved independently. And it cites PMID:41380172 for growth impairment, but that paper is a CUL3 case whose follow-up reports normal growth and appropriate developmental milestones, so it supports neither the growth claim nor anything about the KLHL3 form.

Create: Pseudohypoaldosteronism Type 2D (KLHL3) · 2026-10-30T16:21:33Z · View source

New Disease entry for the KLHL3 form of familial hyperkalemic hypertension, curated from literature plus one openscientist deep-research report. entry_type decided DISEASE; the stub is deleted. Mechanism curated as an eleven-node causal chain from adaptor loss through failed CUL3-KLHL3 ubiquitination of WNK1/WNK4, SPAK and OSR1 hyperactivation and NCC hyperphosphorylation to the three clinical branches. Both inheritance modes encoded with HPO bindings and separate evidence, the dominant one as a dominant-negative dimer node supported by the knockout mouse asymmetry. Two animal models with modeled_mechanisms, including a FAILS_TO_RECAPITULATE link with a typed PROXY_QUANTITY divergence on the heterozygous null. Four discussions: three KNOWLEDGE_GAP (acidosis mechanism, hypercalciuria mechanism, recessive missense versus null) and one OPEN_QUESTION on upstream cascade inhibitors. The deep-research report gave KLHL3 as HGNC:15531 (EBNA1BP2) and mislabelled two HPO terms; all CURIEs were resolved independently and the rejections recorded in notes. Validation: just validate, validate-terms, count-verified-snippets (142/142), validate-disorders (142 snippets, 143 titles, 0 issues), check-genereviews --online (chapter PMID:22073419 tagged), and the offline gate battery, all passing.

OpenScientist ▸

Pseudohypoaldosteronism Type 2D (PHA2D): A Comprehensive Disease Characteristics Report

openscientist-autonomous 22 citations 2026-10-30T15:46:07.907946

Pseudohypoaldosteronism Type 2D (PHA2D): A Comprehensive Disease Characteristics Report

Disease: Pseudohypoaldosteronism Type 2D (PHA2D) Causal gene: KLHL3 (Kelch-like family member 3; HGNC:15531; UniProt Q9UH77; locus 5q31.2) MONDO: MONDO:0013781 | OMIM: 614495 | Category: Mendelian

Summary

Pseudohypoaldosteronism type 2D (PHA2D) is a rare monogenic form of familial hyperkalemic hypertension (FHHt), also known as Gordon syndrome or pseudohypoaldosteronism type II (PHAII), caused by germline mutations in KLHL3. KLHL3 encodes the kelch-domain substrate adaptor of a Cullin-3 (CUL3)-based E3 ubiquitin ligase whose physiological job in the distal nephron is to bind and ubiquitinate the serine-threonine kinases WNK1 and WNK4, targeting them for proteasomal degradation. When KLHL3 loses the ability to bind its WNK substrates (or to engage CUL3), WNK kinase levels rise. The excess WNK signal activates the SPAK/OSR1 kinases, which phosphorylate and activate the thiazide-sensitive Na-Cl cotransporter (NCC, SLC12A3) in the distal convoluted tubule. The net result is a stereotyped clinical triad: salt-sensitive, low-renin hypertension; hyperkalemia; and hyperchloremic (type-4) metabolic acidosis, with aldosterone that is inappropriately normal rather than elevated — hence "pseudohypoaldosteronism."

PHA2D is distinctive among the four FHHt genes (WNK1, WNK4, KLHL3, CUL3) in that it can be inherited in both autosomal dominant and autosomal recessive fashion. Dominant missense variants cluster in the kelch propeller and BTB domains (the substrate- and cullin-binding surfaces); recessive disease typically arises in consanguineous families. The mechanism has been validated extensively in human genetics, knock-in mouse models that reproduce the full triad, structural/biochemical studies, and cell biology, converging on a single, coherent causal chain. Importantly, because the pathway terminates in NCC gain-of-function, the disease is fully and specifically reversed by low-dose thiazide diuretics and/or dietary salt restriction, making PHA2D one of the few forms of hypertension with a precise, mechanism-based cure.

This report consolidates ten confirmed findings across 34 reviewed papers into a complete disease knowledge-base entry covering etiology, phenotypes, molecular genetics, pathophysiology (as an ordered causal chain), affected anatomy, temporal course, epidemiology, diagnostics, prognosis, treatment, prevention, and model systems.

Key Findings

Finding 1 — KLHL3 mutations cause PHA2D by impairing WNK kinase ubiquitination in the distal nephron

Exome sequencing of PHAII patients from 41 unrelated families identified mutations in KLHL3 or CUL3 as causes of the disorder, establishing KLHL3 as a bona fide FHHt gene (PMID: 22266938). A key quote: "Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo." An independent linkage-plus-exome study identified KLHL3 as a third FHHt gene, reporting 11 additional missense mutations and showing that "the KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes. KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface" (PMID: 22406640). A mechanistic review confirmed the loss-of-degradation principle: "In PHAII, the loss of interaction between KLHL3 and WNK4 induces increased levels of WNK kinases due to impaired ubiquitination" (PMID: 26152401). Together these establish KLHL3 as the CUL3 substrate adaptor whose loss-of-function raises WNK abundance.

Finding 2 — KLHL3-WNK4 binding is physiologically regulated by angiotensin II/PKC phosphorylation at Ser433

The KLHL3-WNK4 interaction is not static but hormonally tuned. KLHL3 is phosphorylated at serine 433 in the kelch domain by protein kinase C (PKC), which prevents WNK4 binding and degradation; angiotensin II drives this phosphorylation in vivo, raising WNK4 and NCC levels (PMID: 25313067): "We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation." Strikingly, Ser433 is itself a residue frequently mutated in PHAII — so a pathogenic mutation at S433 mimics the constitutively phosphorylated (binding-incompetent) state. The opposing phosphatase is calcineurin, which dephosphorylates KLHL3; this explains why calcineurin inhibitors (tacrolimus, cyclosporine) phenocopy PHAII hypertension and hyperkalemia via NCC activation (PMID: 30718414): "WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4's ubiquitylation and proteasomal degradation." A molecular dynamics study provided the structural basis: "phosphorylation of KLHL3 at S433 disrupts the hydrogen bonds, hydrophobic and electrostatic interactions between the Kelch domain of KLHL3 and the AM of WNK4" (PMID: 27727489) — the phospho-group makes the acidic-motif binding pocket more electronegative, abolishing substrate binding.

Finding 3 — KLHL3(R528H/+) knock-in mice recapitulate the full PHA2D triad

Direct causal proof comes from a knock-in mouse carrying a dominant human KLHL3 mutation. KLHL3(R528H/+) mice developed "salt-sensitive hypertension, hyperkalemia and metabolic acidosis" — the complete PHAII triad — and "the phosphorylation of NCC was increased in the KLHL3(R528H/+) mouse kidney" (PMID: 24821705). The upstream lesion was confirmed biochemically: "the protein expression of both WNK1 and WNK4 was significantly increased in the KLHL3(R528H/+) mouse kidney." The R528H mutant KLHL3 showed impaired binding to WNK1/WNK4 peptides. This study closes the loop from mutation → impaired WNK binding → WNK accumulation → NCC hyperphosphorylation → clinical triad in a single intact mammalian model.

Finding 4 — PHA2D is one of four FHHt/Gordon syndrome genes; KLHL3 is unique in showing both dominant and recessive inheritance

Gordon syndrome/FHHt is caused by variants in four genes — WNK1, WNK4, KLHL3, and CUL3 — all converging on NCC activation (PMID: 31795491; PMID: 23683032). KLHL3 is the only one of the four that shows both autosomal dominant and autosomal recessive inheritance (PMID: 22266938). In a UK FHHt cohort, "we have identified novel disease-causing variants in CUL3 and KLHL3 segregating in 63% of the pedigrees with previously unexplained FHHt", and importantly "KLHL3 variants all occur in kelch-repeat domains and so probably disrupt WNK complex binding" (PMID: 24266877). Dominant missense mutations cluster in short segments of the kelch propeller and BTB domains (substrate- and cullin-binding surfaces) and phenocopy recessive loss of function.

Finding 5 — Thiazide diuretics are the definitive, mechanism-based treatment

Because the entire pathway terminates in NCC gain-of-function, the thiazide class — which directly inhibits NCC — is curative. "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). FHHt is "effectively treated by thiazide diuretics and/or dietary salt restriction" (PMID: 24266877). However, thiazides have limitations: "Thiazide diuretics are currently the main treatment option for Gordon's syndrome. However, they have a number of side effects, and chronic usage can lead to compensatory adaptations in the nephron" (PMID: 32724175), which is motivating development of direct WNK-SPAK/OSR1 inhibitors.

Finding 6 — Clinical/laboratory phenotype: hyperkalemia + hypertension + hyperchloremic metabolic acidosis with suppressed renin and preserved GFR

"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" (PMID: 41380172). Aldosterone is inappropriately normal (not elevated) despite hyperkalemia — the "pseudohypoaldosteronism" paradox. In pediatric patients, "persistent metabolic acidosis and hypertension may lead to significant growth and developmental impairments" (PMID: 41380172), supporting short stature/growth impairment as a downstream consequence. Genetic testing is emphasized as "indispensable for precise subtyping" and prognostication (PMID: 41982973). Hypercalciuria is a recognized feature of pseudohypoaldosteronism (PMID: 16357816).

Finding 7 — Variant spectrum and urinary NCC biomarker

Specific KLHL3 variants include the dominant Q309R and the recessive S553L. A consanguineous Jewish family of Yemenite extraction carrying S553L included "2 homozygous and 7 heterozygous affected subjects" (PMID: 28511177). Increased urinary exosomal NCC was detected in affected members with the dominant Q309R variant and in homozygotes (and some heterozygotes) in the recessive family — providing a functional biomarker that directly reflects the pathway's NCC gain-of-function. KLHL3 disease is "mostly dominant" with a few recessive cases, and consanguinity underlies the recessive form. Pathogenic KLHL3 variants are predominantly missense in kelch-repeat/BTB domains (PMID: 24266877).

Finding 8 — The WNK-OSR1/SPAK-NCC cascade is necessary and sufficient for the phenotype downstream of KLHL3/WNK dysregulation

Genetic epistasis experiments pinpoint the effector pathway. In Wnk4(D561A/+) PHAII mice, deleting SPAK abolished the phenotype: "Wnk4 (D561A/+).Spak (-/-) mice became normotensive and lacked the PHA II phenotype" (PMID: 24039833), whereas kidney-specific Osr1 knockout did not rescue — identifying SPAK as the principal effector kinase. Triple knock-in mice preventing SPAK/OSR1 activation almost completely abolished NCC phosphorylation and corrected the triad: "the high blood pressure, hyperkalemia and metabolic acidosis observed in Wnk4(D561A/+) mice were corrected in the triple knock-in mice. These results clearly establish that PHAII caused by the WNK4 D561A mutation is dependent on the activation of the WNK-OSR1/SPAK-NCC cascade" (PMID: 21486947). The cascade is physiologically regulated by dietary salt and aldosterone (PMID: 18800028). KLHL3 acts upstream by controlling WNK abundance, feeding into this same shared effector pathway.

Finding 9 — Hyperkalemia and acidosis arise from WNK-mediated suppression of distal K⁺/H⁺ secretion plus reduced Na⁺ delivery

The hyperkalemia/acidosis branch is mechanistically separable from the hypertension branch. WNK4 (stabilized when KLHL3 is mutated) "is a serine-threonine kinase expressed in the distal nephron that inhibits ROMK activity and renal K(+) secretion" (PMID: 23885063) and also inhibits the large-conductance BK/Maxi-K channel by promoting its ubiquitin-/lysosome-dependent degradation (PMID: 21613417). A review confirms: "WNK4 also regulates the expression or function of renal outer medullary potassium (ROMK) channels, ENaCs, and Cl transporters. WNK1 also regulates NCC and ROMK. Aldosterone inactivates WNK1 and WNK4 activity" (PMID: 20829405). Mouse models implicate ROMK and maxi-K dysregulation in producing hyperkalemia (PMID: 19448535). In parallel, enhanced upstream NCC activity reduces Na⁺ delivery to the aldosterone-sensitive distal nephron, diminishing the electrochemical driving force for both K⁺ and H⁺ secretion.

Finding 10 — Synthesis: a thiazide-reversible distal-nephron channelopathy of impaired WNK-kinase ubiquitination

Integrating human genetics, mouse models, cell biology, and clinical reports: KLHL3 (HGNC:15531, UniProt Q9UH77, 5q31.2) is the CUL3-ligase adaptor whose loss-of-function (dominant or recessive) raises WNK1/WNK4, activating SPAK/OSR1→NCC (driving hypertension) while suppressing ROMK/BK and reducing distal Na⁺ delivery (driving hyperkalemia and type-4 acidosis). Renin is suppressed and aldosterone inappropriately normal. The anchoring evidence: "Disease features are reversed by thiazide diuretics... KLHL3 and CUL3 are expressed in this location" (PMID: 22266938) and "KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface" (PMID: 22406640).

Section-by-Section Report

1. Disease Information

PHA2D is a rare, Mendelian, salt-retaining tubulopathy — a subtype of familial hyperkalemic hypertension (FHHt) / Gordon syndrome / pseudohypoaldosteronism type II (PHAII) — specifically caused by mutations in KLHL3. It is defined by renal tubular gain of NaCl reabsorption with impaired K⁺ and H⁺ excretion, producing hypertension, hyperkalemia, and metabolic acidosis in the face of normal glomerular filtration.

Key identifiers:

Resource	Identifier
OMIM	614495
MONDO	MONDO:0013781
Gene (HGNC)	KLHL3, HGNC:15531
UniProt	Q9UH77
Locus	5q31.2
ICD-10	E26.8 (other mineralocorticoid disorders) — nearest mapping
MeSH	Pseudohypoaldosteronism (D011546)
Orphanet	ORPHA:757 (Gordon hyperkalemia-hypertension syndrome)

Synonyms: PHA2D; KLHL3 pseudohypoaldosteronism type 2; pseudohypoaldosteronism type 2 caused by mutation in KLHL3; a molecular subtype of Gordon syndrome / Familial Hyperkalemic Hypertension (FHHt) / PHAII. Information is derived from aggregated disease-level resources (OMIM, gene-discovery cohorts) and individual patient/family reports, not from EHR-scale datasets.

2. Etiology

Causal factors: Purely genetic — germline missense mutations in KLHL3. No infectious or environmental cause initiates the disease. Dominant mutations cluster in the kelch-repeat propeller (substrate-binding) and BTB (CUL3-binding) domains; recessive mutations cause loss of function, typically in consanguineous families (PMID: 22266938; PMID: 24266877).

Genetic risk factors: The KLHL3 mutation is the sole driver; there are no documented susceptibility loci beyond the four FHHt genes (WNK1, WNK4, KLHL3, CUL3). Modifier: background NCC/SLC12A3 genotype could in principle modulate severity (NCC phosphorylation state governs the phenotype), though this is inferred, not demonstrated for KLHL3 specifically.

Environmental/lifestyle modifiers: Dietary salt is the key modifiable factor — the phenotype is salt-sensitive, worsened by high Na⁺ intake and improved by salt restriction (PMID: 18800028). Angiotensin II and calcineurin-inhibitor drugs (tacrolimus/cyclosporine) phenocopy/aggravate the mechanism by shifting KLHL3 phosphorylation toward the WNK4-binding-incompetent state (PMID: 25313067; PMID: 30718414).

Protective factors: A low-sodium diet is protective (reduces NCC-mediated salt retention). Loss-of-function in the downstream SPAK kinase would be protective (abolishes the phenotype in mice) — the pharmacological rationale for SPAK/OSR1 inhibitors.

Gene–environment interaction: A clear GxE axis exists — the genetic lesion (KLHL3 loss-of-function) raises the setpoint of the WNK-SPAK-NCC cascade, but dietary salt and aldosterone/AngII tone determine the degree of expression. Calcineurin inhibitors convert a drug exposure into a biochemical phenocopy, demonstrating convergence of pharmacologic and genetic inputs on the same node.

3. Phenotypes

Phenotype	Type	HPO term	Onset / severity / frequency
Hyperkalemia	Lab abnormality	HP:0002153	Often earliest/most constant sign; frequently neonatal–childhood; near-universal
Hypertension	Clinical sign	HP:0000822	Variable; may be later-onset than hyperkalemia; common but can be mild/absent in young recessive cases
Hyperchloremic metabolic acidosis (type-4 RTA)	Lab abnormality	HP:0004910 / HP:0001942	Common; contributes to growth impairment
Suppressed plasma renin	Lab abnormality	HP:0040331 (abnormal renin)	Characteristic
Inappropriately normal aldosterone	Lab abnormality	—	Characteristic ("pseudo" feature)
Hypercalciuria	Lab abnormality	HP:0002150	Recognized feature (PMID: 16357816)
Short stature / growth impairment	Physical	HP:0004322	In pediatric cases with persistent acidosis (PMID: 41380172)
Muscle weakness (hyperkalemia-related)	Symptom	HP:0001324	Variable/episodic

Characteristics: Age of onset ranges from neonatal/childhood (hyperkalemia often first) to adult (hypertension); severity is variable and genotype-dependent; course is chronic and stable/lifelong rather than episodic; renal function is preserved. Quality-of-life impact is driven chiefly by hyperkalemia risk (arrhythmia, muscle weakness), hypertension-related cardiovascular risk, and, in children, growth/developmental impairment — all largely correctable with treatment.

4. Genetic / Molecular Information

Causal gene: KLHL3 (HGNC:15531; UniProt Q9UH77; chromosome 5q31.2). Protein: a BTB-BACK-kelch substrate adaptor that recruits WNK1/WNK4 for a CUL3-based E3 ubiquitin ligase.

Variant classes: Predominantly missense variants in the kelch-repeat propeller (substrate binding) and BTB (CUL3 binding) domains. Representative variants: R528H (dominant; validated in knock-in mice, PMID: 24821705), Q309R (dominant, PMID: 28511177), S553L (recessive, PMID: 28511177), and the regulatory hotspot S433 (dominant; phosphomimetic effect, PMID: 25313067). Classification: pathogenic/likely pathogenic per segregation and functional data. Allele frequency: extremely rare in gnomAD (private/family-specific). Origin: germline. Functional consequence: loss of function of KLHL3's WNK-degradation activity — dominant variants act by dominant-negative/haploinsufficiency on substrate or cullin binding; recessive variants require biallelic loss.

Modifier genes: The downstream SPAK (STK39), OSR1 (OXSR1), NCC (SLC12A3), WNK1, and WNK4 set phenotype magnitude. Epigenetic/chromosomal abnormalities: none described — PHA2D is a single-gene point-mutation disorder, not a copy-number/structural disease.

5. Environmental Information

PHA2D is genetically determined; the only clinically important non-genetic contributors are dietary sodium (aggravates), angiotensin II tone, and calcineurin-inhibitor drugs (tacrolimus/cyclosporine), which phenocopy the biochemical lesion by dephosphorylation-blockade of KLHL3 (PMID: 30718414). There are no infectious agents involved.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

A germline KLHL3 missense mutation (dominant in kelch/BTB domains, or biallelic recessive) leads to loss of KLHL3's ability to bind WNK1/WNK4 (or to engage CUL3). (Demonstrated: impaired peptide binding, PMID: 24821705.)
Impaired substrate binding results in failure of CUL3-KLHL3-mediated ubiquitination of WNK1/WNK4. (Demonstrated, PMID: 26152401.)
Failed ubiquitination leads to accumulation of WNK1 and WNK4 protein in the distal convoluted tubule. (Demonstrated in vivo: both WNK1 and WNK4 increased in KLHL3(R528H/+) kidney, PMID: 24821705.)
Elevated WNK kinases activate the STE20-family kinases SPAK (and OSR1). (Demonstrated; SPAK is the principal effector, PMID: 24039833.)
Activated SPAK/OSR1 phosphorylate and activate the Na-Cl cotransporter NCC at the apical membrane. (Demonstrated: increased p-NCC, PMID: 24821705; PMID: 21486947.)

Branch A (hypertension): Enhanced NCC-mediated NaCl reabsorption leads to plasma volume expansion → salt-sensitive, low-renin hypertension.

Branch B (hyperkalemia + acidosis): Two parallel sub-mechanisms: - 6a. Elevated WNK4 directly inhibits ROMK and promotes degradation of BK/Maxi-K channels, reducing distal K⁺ secretion → hyperkalemia (PMID: 23885063; PMID: 21613417). - 6b. Increased upstream NCC activity reduces Na⁺ delivery to the aldosterone-sensitive distal nephron, diminishing the electrochemical driving force (ENaC-dependent lumen-negativity) for K⁺ and H⁺ secretion → hyperkalemia and hyperchloremic (type-4) metabolic acidosis (PMID: 19448535; PMID: 20829405). 7. Volume expansion suppresses renin; hyperkalemia should raise aldosterone, but aldosterone is inappropriately normal — the "pseudohypoaldosteronism" paradox.

KLHL3 mutation
      │ (loss of WNK binding / ubiquitination)
      ▼
 ↑ WNK1 / WNK4  ───►  ↑ SPAK/OSR1  ───►  ↑ p-NCC (active)
      │                                        │
      │                          ┌─────────────┴─────────────┐
      │                          ▼                           ▼
      │                  ↑ NaCl reabsorption        ↓ Na+ delivery to ASDN
      │                          │                           │
      │                          ▼                           ▼
      │                  volume expansion            ↓ K+/H+ secretion
      │                          │                           │
      ▼                          ▼                           ▼
 ↓ ROMK, ↓ BK  ──────►   LOW-RENIN HYPERTENSION    HYPERKALEMIA + ACIDOSIS
   (↓ K+ secretion)

Regulatory overlay: KLHL3-WNK4 binding is normally switched off by AngII/PKC phosphorylation at Ser433 and switched on by calcineurin dephosphorylation — so AngII and calcineurin inhibitors push the system toward the PHA2D state even without a mutation (PMID: 25313067; PMID: 30718414; PMID: 27727489).

Pathway/ontology annotations: Molecular pathway — CUL3-KLHL3 E3 ubiquitin ligase / WNK-SPAK/OSR1-NCC signaling. GO terms: protein polyubiquitination (GO:0000209), protein K48-linked ubiquitination (GO:0070936), Cul3-RING ubiquitin ligase complex (GO:0031463), sodium ion transmembrane transport (GO:0035725), potassium ion transmembrane transport (GO:0071805), regulation of blood pressure (GO:0008217). Protein dysfunction: loss of adaptor function (substrate/cullin binding). Biochemical abnormality: ion-transporter dysregulation (NCC gain; ROMK/BK loss). No autoimmunity, metabolic-enzyme deficiency, or inflammatory component. CHEBI entities: potassium(1+) (CHEBI:29103), chloride (CHEBI:17996), sodium(1+) (CHEBI:29101), aldosterone (CHEBI:27584).

7. Anatomical Structures Affected

Organ: Kidney (UBERON:0002113), specifically the distal convoluted tubule (UBERON:0001292) and the aldosterone-sensitive distal nephron / connecting tubule–cortical collecting duct.
Body system: Renal/urinary and endocrine (mineralocorticoid axis); secondary cardiovascular involvement (hypertension) and growth/skeletal effects in children.
Cell type: Distal convoluted tubule epithelial cell (CL:1000849 / kidney DCT cell), where KLHL3 is coexpressed with NCC (PMID: 22406640); and principal cells of the collecting duct (site of ROMK/ENaC-dependent K⁺/H⁺ handling).
Tissue: renal tubular epithelium.
Subcellular (GO Cellular Component): apical plasma membrane (GO:0016324) — NCC, ROMK, BK localization; cytoplasm — WNK/SPAK signaling; Cul3-RING ligase complex (GO:0031463).
Lateralization: bilateral (systemic genetic disorder affecting both kidneys).

8. Temporal Development

Onset: Variable and biphasic — hyperkalemia often appears first in childhood (sometimes neonatally), while hypertension frequently develops later (adolescence/adulthood). Onset is insidious/chronic, not acute. A 9-year follow-up of early-onset PHA2 documents childhood presentation (PMID: 41380172).

Progression: Slow, stable, chronic and lifelong; not relapsing-remitting or episodic. Renal function is typically preserved. Untreated persistent acidosis/hypertension in childhood can impair growth. Remission is treatment-induced (thiazide/salt restriction), not spontaneous. Critical period: early recognition in childhood is the key window to prevent growth impairment and long-term cardiovascular damage.

9. Inheritance and Population

Epidemiology: PHA2/Gordon syndrome is rare (Orphanet ORPHA:757); precise prevalence/incidence figures for the KLHL3 (PHA2D) subtype are not established — reported as scattered families and small case series. Among FHHt cohorts, KLHL3/CUL3 variants explained ~63% of previously unexplained pedigrees (PMID: 24266877).

Inheritance: Both autosomal dominant and autosomal recessive — unique to KLHL3 among FHHt genes (PMID: 22266938). Dominant disease is "mostly" the rule; recessive disease arises with consanguinity (e.g., S553L in a consanguineous Yemenite Jewish family with 2 homozygous + 7 heterozygous affected, PMID: 28511177). Penetrance: high but with variable expressivity (age-dependent for hypertension). Founder effects: plausible in consanguineous recessive kindreds. Genetic anticipation / mitochondrial inheritance / germline mosaicism: not features of this disorder. Sex ratio: no strong predilection reported. Carrier frequency: very low (private variants).

10. Diagnostics

Laboratory (core): serum K⁺ (↑), serum HCO₃⁻ (↓)/Cl⁻ (↑) indicating hyperchloremic metabolic acidosis, plasma renin (↓/suppressed), aldosterone (inappropriately normal), normal creatinine/eGFR; blood-pressure monitoring. LOINC-type analytes: potassium serum (2823-3), bicarbonate (1963-8), renin, aldosterone. Biomarker: increased urinary exosomal NCC reflects pathway activation and can distinguish affected members (PMID: 28511177).

Genetic testing (confirmatory and essential): "genetic testing is indispensable for precise subtyping" (PMID: 41982973). Approach: targeted single-gene or FHHt/Gordon gene-panel sequencing (WNK1, WNK4, KLHL3, CUL3), or whole-exome sequencing for undiagnosed familial hyperkalemic hypertension (the original discovery method, PMID: 22266938). CMA/karyotype/FISH/mtDNA/repeat-expansion testing are not applicable (point-mutation disorder).

Clinical criteria / differential diagnosis: Diagnose by the triad of hyperkalemia + (hyper)tension + hyperchloremic metabolic acidosis with suppressed renin, normal GFR, and inappropriately normal aldosterone. Differentials: PHA type I / adrenal insufficiency (salt-wasting, low BP — opposite), chronic kidney disease (abnormal GFR), Addison disease, drug-induced hyperkalemia (ACEi/ARB/K-sparing diuretics, calcineurin inhibitors), and the other FHHt genes (WNK1/WNK4/CUL3) — distinguished by genetic testing. Screening: cascade genetic/biochemical screening of first-degree relatives in known families.

11. Outcome / Prognosis

Prognosis is excellent with treatment. There is no inherent reduction in life expectancy when hyperkalemia and hypertension are controlled; renal function is generally preserved. Morbidity without treatment stems from hyperkalemia (arrhythmia, muscle weakness), hypertension-related cardiovascular/end-organ risk, and — in children — growth and developmental impairment from persistent acidosis (PMID: 41380172). Recovery potential is high: biochemical and blood-pressure abnormalities are fully reversible on thiazide/salt restriction (PMID: 22266938). Prognostic factors: genotype (dominant vs recessive; specific variant), age at diagnosis, and treatment adherence.

12. Treatment

First-line / definitive — Thiazide diuretics (e.g., hydrochlorothiazide, chlorthalidone) directly inhibit NCC, the pathway endpoint, reversing all three disease features (PMID: 22266938; PMID: 24266877). NCIT: Thiazide Diuretic (C29723); Hydrochlorothiazide (C29281). Adjunct — dietary sodium restriction (mechanistically synergistic). Thiazides correct hyperkalemia (by restoring distal Na⁺ delivery/flow-dependent K⁺ secretion), acidosis, and hypertension simultaneously.

Limitations and emerging therapy: Chronic thiazide use has side effects and provokes compensatory nephron adaptation (PMID: 32724175); direct WNK-SPAK/OSR1 inhibitors are in development as mechanism-targeted alternatives. Avoid agents that aggravate the mechanism: ACE inhibitors/ARBs are not first-line (renin already suppressed), and calcineurin inhibitors phenocopy the lesion (PMID: 30718414). Supportive: monitor potassium and blood pressure; treat pediatric acidosis to protect growth. Gene/cell/RNA therapies are not applicable/available for this condition.

13. Prevention

PHA2D cannot be prevented at the genetic level, but complications are highly preventable. Primary prevention does not apply (monogenic). Secondary prevention: cascade biochemical + genetic screening of relatives in known kindreds enables pre-symptomatic diagnosis and early thiazide/salt-restriction intervention. Tertiary prevention: ongoing control of K⁺ and blood pressure to prevent arrhythmia, cardiovascular damage, and (in children) growth failure. Genetic counseling should address the dual AD/AR inheritance — autosomal dominant transmission (50% offspring risk) in most families, and recessive risk with consanguinity (PMID: 28511177). Prenatal/preimplantation testing is technically feasible once the familial variant is known. No immunization or public-health/environmental intervention applies.

14. Other Species / Natural Disease

Orthologs: KLHL3 is conserved in mouse (Klhl3), rat, and other vertebrates; the entire CUL3-KLHL3-WNK-SPAK-NCC axis is evolutionarily conserved, which is why mouse models faithfully reproduce the human disease (PMID: 24821705). NCBI Taxon: human (9606), mouse (10090). Natural disease in companion animals/wildlife: no naturally occurring KLHL3 PHA2D is documented in OMIA. Zoonotic potential: none (non-transmissible genetic disorder).

15. Model Organisms

Model	Type	Phenotype recapitulation	Reference
KLHL3(R528H/+) knock-in mouse	Mammalian, dominant knock-in	Full triad — salt-sensitive hypertension, hyperkalemia, metabolic acidosis; ↑WNK1/WNK4; ↑p-NCC	PMID: 24821705
Wnk4(D561A/+) knock-in mouse	Mammalian (WNK4 FHHt model, shared effector pathway)	Full PHAII triad; salt/aldosterone-regulated cascade	PMID: 21486947; PMID: 18800028
Wnk4(D561A/+);Spak⁻/⁻	Genetic epistasis cross	Normotensive, phenotype abolished — proves SPAK is effector	PMID: 24039833
SPAK/OSR1 triple knock-in	Mammalian	Corrects BP, hyperkalemia, acidosis	PMID: 21486947
Xenopus oocytes / HEK293 cells	In vitro	Quantify NCC surface expression, WNK ubiquitination, KLHL3 binding	PMID: 22406640

The KLHL3(R528H/+) knock-in mouse is the direct, high-fidelity model of PHA2D, recapitulating both the biochemistry (WNK accumulation, NCC hyperphosphorylation) and the clinical triad. Limitation: mouse models emphasize the hypertension/NCC branch; the human severity balance of hyperkalemia vs hypertension is genotype-variable and incompletely captured. Resources: MGI, IMPC, IMSR.

Mechanistic Model / Interpretation

PHA2D is best understood as a "loss of a brake on salt reabsorption." Normally, the CUL3-KLHL3 E3 ligase continuously degrades WNK1/WNK4 kinases, keeping the WNK-SPAK/OSR1-NCC salt-reabsorption cascade restrained and tunable by salt, aldosterone, and angiotensin II. A KLHL3 mutation removes this brake: WNK kinases accumulate, the cascade runs hot, and NCC over-reabsorbs NaCl. The disease then splits into two mechanistically distinct but linked branches from the single node of excess WNK/NCC activity: a volume/pressure branch (hypertension, renin suppression) and a potassium/acid branch (hyperkalemia, type-4 acidosis), the latter arising both from direct WNK4 inhibition of ROMK/BK channels and from reduced distal Na⁺ delivery that starves the K⁺/H⁺ secretory driving force. The elegance — and therapeutic key — is that everything funnels through NCC, so a thiazide (or salt restriction) that blocks NCC corrects the entire syndrome at once. The S433/PKC/calcineurin regulatory layer unifies the Mendelian disease with acquired phenocopies (calcineurin-inhibitor toxicity, AngII-driven salt-sensitive hypertension), giving PHA2D outsized importance as a model for common essential hypertension.

Evidence Base

PMID	Contribution	Supports
22266938	KLHL3/CUL3 gene discovery; dual AD/AR; thiazide reversibility	F001, F004, F005, F010
22406640	KLHL3 as CUL3 adaptor; coexpressed with NCC; downregulates NCC	F001, F010
26152401	Loss of KLHL3-WNK4 interaction raises WNK	F001
25313067	S433 PKC phosphorylation blocks WNK4 binding	F002
30718414	Calcineurin dephosphorylates KLHL3; CNI phenocopy	F002
27727489	Structural basis of S433 disruption	F002
24821705	KLHL3(R528H/+) mouse; full triad; ↑WNK1/4; ↑p-NCC	F003
24266877	63% FHHt yield; kelch-repeat variants; thiazide/salt treatment	F004, F005, F007
31795491 / 23683032	Four-gene FHHt framework; SPAK intermediary	F004, F008
32724175	Thiazide limitations; WNK-SPAK/OSR1 inhibitors	F005
41380172	Clinical phenotype; growth impairment; 9-yr follow-up	F006
41982973	Genetic testing indispensable for subtyping	F006
28511177	Q309R (dom) vs S553L (rec); urinary NCC biomarker	F007
24039833	SPAK deletion abolishes PHAII	F008
21486947	Triple KI proves cascade dependence	F008
23885063 / 21613417	WNK4 inhibits ROMK and BK	F009
20829405 / 19448535	WNK regulation of distal channels; Na delivery/flow	F009
18800028	Salt/aldosterone regulate the cascade	F008

Limitations and Knowledge Gaps

Epidemiology is unquantified. No reliable prevalence/incidence figures exist for the KLHL3 subtype specifically; the disease is reported as families and small case series.
Genotype–phenotype correlation is incomplete. Why some patients present chiefly with hyperkalemia and others with hypertension, and how dominant vs recessive variants and specific residues (Q309R, R528H, S553L, S433) tune severity, is not fully mapped.
Mouse models over-represent the NCC/hypertension branch and may under-represent the human hyperkalemia phenotype.
No large natural-history or quality-of-life cohort exists for PHA2D; growth-impairment data come from limited pediatric reports.
Human functional data for many KLHL3 variants remain at the in-vitro/computational level; several variants are inferred pathogenic by analogy and segregation rather than individually functionally proven.

Proposed Follow-up Experiments / Actions

Assemble an international PHA2D registry linking KLHL3 genotype (dominant/recessive, residue) to quantitative phenotype (K⁺, BP, HCO₃⁻, height-SDS) to establish penetrance, expressivity, and genotype–phenotype rules.
Deep-mutational scanning of KLHL3 (kelch + BTB domains) with a WNK4-binding/ubiquitination readout to prospectively classify VUS and refine ACMG calls.
Validate urinary exosomal NCC as a routine functional biomarker for diagnosis, carrier detection, and treatment monitoring across both dominant and recessive families.
Clinical evaluation of WNK-SPAK/OSR1 inhibitors in FHHt/PHA2D as thiazide-sparing, mechanism-targeted therapy, with endpoints for hyperkalemia correction and nephron adaptation.
Generate recessive-allele knock-in mice (e.g., S553L homozygous) to test whether recessive loss-of-function produces a distinct (more hyperkalemia-weighted) phenotype than dominant R528H.
Prospective pediatric study of acidosis correction and catch-up growth to define the critical treatment window for preventing developmental impairment.

Report compiled from 10 confirmed findings across 34 reviewed papers (5 investigation iterations). Evidence spans human genetics, knock-in mouse models, structural/molecular dynamics, in vitro cell biology, and clinical case series.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	22
Resolved	22
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	22
On topic	17
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:19448535 (6 mentions) - Distal potassium handling based on flow modulation of maxi-K channel activity.
shared terms: hyperkalemia

Weighed against this report's own most characteristic terms: klhl3, ncc, hyperkalemia, hypertension, dominant, wnk4, acidosis, pha2d, recessive, genetic, disease, wnk1, fhht, cul3, aldosterone, gene, osr1, mutation, phenotype, wnk.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	25
Resolved	23
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	9
Terms named correctly	1
Terms named as a different term	7
Terms whose name is worth a second look	1

Terms the report names something else

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:0013781 (2 mentions) - the report calls it "MONDO"; MONDO calls it pseudohypoaldosteronism type 2D
HP:0002153 (1 mention) - the report calls it "Lab abnormality"; HP calls it Hyperkalemia
HP:0000822 (1 mention) - the report calls it "Clinical sign"; HP calls it Hypertension
HP:0040331 (1 mention) - the report calls it "abnormal renin"; HP calls it Focal hypointensity of cerebral white matter on MRI
HP:0002150 (1 mention) - the report calls it "Lab abnormality"; HP calls it Hypercalciuria
HP:0004322 (1 mention) - the report calls it "Physical"; HP calls it Short stature
HP:0001324 (1 mention) - the report calls it "Symptom"; HP calls it Muscle weakness

Terms whose name is worth a second look

The 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:

UBERON:0002113 (1 mention) - the report calls it "Kidney", "Organ: Kidney"; UBERON calls it kidney

Terms named inconsistently

The report gives these identifiers more than one name of its own:

UBERON:0002113 - called "Kidney", "Organ: Kidney"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Deep Research

Pseudohypoaldosteronism Type 2D (PHA2D): A Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — KLHL3 mutations cause PHA2D by impairing WNK kinase ubiquitination in the distal nephron

Finding 2 — KLHL3-WNK4 binding is physiologically regulated by angiotensin II/PKC phosphorylation at Ser433

Finding 3 — KLHL3(R528H/+) knock-in mice recapitulate the full PHA2D triad

Finding 4 — PHA2D is one of four FHHt/Gordon syndrome genes; KLHL3 is unique in showing both dominant and recessive inheritance

Finding 5 — Thiazide diuretics are the definitive, mechanism-based treatment

Finding 6 — Clinical/laboratory phenotype: hyperkalemia + hypertension + hyperchloremic metabolic acidosis with suppressed renin and preserved GFR

Finding 7 — Variant spectrum and urinary NCC biomarker

Finding 8 — The WNK-OSR1/SPAK-NCC cascade is necessary and sufficient for the phenotype downstream of KLHL3/WNK dysregulation

Finding 9 — Hyperkalemia and acidosis arise from WNK-mediated suppression of distal K⁺/H⁺ secretion plus reduced Na⁺ delivery

Finding 10 — Synthesis: a thiazide-reversible distal-nephron channelopathy of impaired WNK-kinase ubiquitination

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

References that may not be about this subject

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver