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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Pseudohypoaldosteronism Type II

Synonyms: Gordon’s Syndrome, Familial Hyperkalemia and Hypertension, PHAII, PHA2, Pseudohypoaldosteronism Type 2

, MD, PhD and , MD, PhD.

Author Information
, MD, PhD
Department of Medical Oncology
Dana-Farber Cancer Institute
Harvard Medical School
Boston, Massachusetts
, MD, PhD
Department of Neurobiology
Howard Hughes Medical Institute
Harvard Medical School
Manton Center for Orphan Disease
Children’s Hospital Boston
Boston, Massachusetts

Initial Posting: ; Last Update: January 16, 2014.

Summary

Disease characteristics. Pseudohypoaldosteronism type II (PHAII) is characterized by hypertension and hyperkalemia despite normal glomerular filtration rate (GFR). Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion). Hypercalciuria is well described.

Diagnosis/testing. The diagnosis is established by the finding of hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels. Molecular genetic testing of WNK4 and WNK1, the two genes in which mutations are known to cause PHAIIB and PHAIIC, respectively, is possible. Mutations in KLHL3 and CUL3 cause PHAIID and PHAIIE, respectively.

Management. Treatment of manifestations: Electrolyte and blood pressure abnormalities of PHAII in children and adults are corrected with thiazide diuretics.

Prevention of secondary complications: Control of blood pressure is important to reduce the risk of cardiovascular and renal disease and stroke.

Surveillance: Routine electrolyte and blood pressure measurements.

Evaluation of relatives at risk: Measurement of serum potassium concentration and blood pressure of first-degree relatives of individuals with PHAII allows for early diagnosis and treatment

Genetic counseling. All types of PHAII are inherited in an autosomal dominant manner; PHAIID may also be inherited in an autosomal recessive manner. Each child of an individual with autosomal dominant PHAII has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known; however, requests for prenatal testing for conditions which (like PHAII) can be treated effectively are not common.

GeneReview Scope

Pseudohypoaldosteronism Type II: Included Disorders
  • Pseudohypoaldosteronism type IIB
  • Pseudohypoaldosteronism type IIC
  • Pseudohypoaldosteronism type IID
  • Pseudohypoaldosteronism type IIE

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

A diagnosis of pseudohypoaldosteronism type II (PHAII) should be considered with the following clinical presentation:

  • Hyperkalemia in the absence of impaired glomerular filtration
  • Hypertension (blood pressure >140/90 mm Hg) generally manifesting in adolescence or adulthood but also reported in children with PHAII
  • Metabolic acidosis
  • Hyperchloremia
  • Suppressed plasma renin levels
  • A first-degree relative with similar findings
  • Other
    • Serum aldosterone levels are variable but tend to be relatively suppressed in the context of hyperkalemia.
    • Serum calcium and parathyroid hormone levels are normal; however, hypercalciuria is noted in at least a subset of individuals.

Testing

Serum concentration of potassium. Hyperkalemia in PHAII ranges from mild (serum K ~5.0-6.0 mmol/L) to severe (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L).

Serum concentration of bicarbonate. Reported serum bicarbonate levels in PHAII range from 14 to 24 mmol/L (normal range: ~22-29 mmol/L).

Serum concentration of chloride. Reported serum chloride levels in PHAII range from 105 to 117 mmol/L (normal range: ~99-108 mmol/L).

Molecular Genetic Testing

Genes. The genes in which mutations are known to cause pseudohypoaldosteronism type II (PHAII) are:

  • WNK4 (PHA type IIB)
  • WNK1 (PHA type IIC)
  • KLHL3 (PHA type IID)
  • CUL3 (PHA type IIE)

Evidence for additional locus heterogeneity. An additional locus on 1q31-q42 has been identified as harboring a gene associated with PHAIIA [Mansfield et al 1997]. The identity of this gene is unknown. In addition, PHAII has been reported in at least ten families that lack mutations in WNK1, WNK4, KLHL3, or CUL3 [Boyden et al 2012, Glover et al 2014].

Table 1. Summary of Molecular Genetic Testing Used in Pseudohypoaldosteronism Type II

Gene 1 / Phenotype DesignationProportion of PHAII Attributed to Mutations in This GeneTest MethodMutations Detected 2
WNK4 / PHAIIB9 families reported Sequence analysis 3Sequence variants
Sequencing of select exons 4Sequence variants in select exons
WNK1 / PHAIIC2 families reportedSequence analysis 3Sequence variants 4, 5
Deletion/duplication analysis 6Deletions within intron7
KLHL3 / PHAIID46 families reportedNot specified 8Sequence variants 9
CUL3 / PHAIIE22 families reportedNot specified 8Sequence variants 10

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4. All mutations reported to date have been identified in exons 7 and 17.

5. To date no WNK1 coding region mutations have been reported to cause PHAII.

6. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Two large (41-kb and 21-kb) deletions occurring within the 60-kb first intron of WNK1 have been reported (see Molecular Genetics).

8. Refers to methods used in research testing that may include any combination of targeted mutation analysis, mutation scanning, sequence analysis, deletion/duplication testing or other means of molecular genetic testing.

9. Both autosomal dominant and recessive mutations in KLHL3 cause PHAII. Recessive mutations are identified throughout KHL3, while dominant mutations cluster in the regions encoding domains implicated in substrate binding.

10. Reported intronic and exonic mutations in CUL3 cluster within intron 8, exon 9, and intron 9. These alterations impair splicing of exon 9 and cause an in-frame 57-amino acid deletion.

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

Measure blood pressure and perform routine laboratory evaluation of serum potassium, chloride, bicarbonate, and renal function (including blood urea nitrogen [BUN] and creatinine levels).

2.

Sequence selected exons of WNK4.

3.

If no disease causing mutation is identified through sequencing of selected exons of WNK4, perform deletion/duplication analysis of WNK1.

4.

If no disease causing deletion or duplication is found in WNK1, consider full gene sequencing of WNK4, followed by WNK1.

5.

If a mutation is not identified in WNK4 or WNK1, molecular genetic testing for mutations in KLHL3 and/or CUL3 may be available through research laboratories.

Predictive testing for asymptomatic at-risk family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Pseudohypoaldosteronism type II (PHAII) is characterized by hypertension and hyperkalemia despite normal glomerular filtration rate (GFR). The first case report, published in 1964, described an Australian male age 15 years with hyperkalemia, hypertension, and normal GFR [Paver & Pauline 1964]. This cluster of clinical findings was first described as a familial disorder in a large multi-generation Israeli pedigree with autosomal dominant inheritance [Farfel et al 1978]. Since that time, more than 90 individuals and families with PHAII have been reported.

The clinical presentation of PHAII is heterogeneous. The most consistent clinical feature in both children and young adults is hyperkalemia [Gordon 1986]. As with essential hypertension, blood pressure is usually normal in young persons, with hypertension developing later in life. Untreated individuals with elevated blood pressure are at risk of developing complications of hypertension including cardiac disease, renal impairment, and stroke.

Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion). Hypercalciuria is also well described in PHAII [Mayan et al 2004].

Other features reported in a subset of individuals with PHAII include short stature, myalgias, periodic paralysis, and dental abnormalities [Gordon 1986]. It has been suggested that these findings may be more prevalent in individuals with severe hyperkalemia and metabolic acidosis; however, exceptions have been reported [Gordon 1986, Farfel et al 2011].

Genotype-Phenotype Correlations

Compared with those harboring WNK1, WNK4, or KLHL3 alterations, individuals with CUL3 mutations tend to have more severe hyperkalemia and metabolic acidosis, earlier development of hypertension, and greater likelihood of growth impairment [Boyden et al 2012]. In general, clinical manifestations of PHAII appear to be milder in individuals with WNK1 and WNK4 mutations than in those with KLHL3 or CUL3 mutations [Boyden et al 2012].

Penetrance

Penetrance of the disorder is high.

Nomenclature

The term “pseudohypoaldosteronism” has historically been used to describe the finding of persistent hyperkalemia despite the presence of normal or elevated serum levels of aldosterone [Schambelan et al 1981]. The term was initially used to describe persons with an inherited disorder characterized by hyperkalemia, elevated serum aldosterone, and volume depletion (now referred to as pseudohypoaldosteronism type I).

As others have pointed out, the term “pseudohypoaldosteronism” is a misnomer in the context of PHAII as affected individuals have hyperkalemia with hypertension (instead of volume depletion).

Prevalence

The prevalence of the disorder is unknown. To date more than 90 individuals and families with PHAII have been reported.

There are no apparent differences with respect to gender or ethnicity.

Differential Diagnosis

See Pseudohypoaldosteronism, Type II: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Hyperkalemia resulting from the following can generally be distinguished from hyperkalemia caused by PHAII on the basis of plasma renin levels, which are increased in the following conditions and suppressed in PHAII.

Other causes of hyperkalemia:

  • Renal insufficiency, the most commonly identified cause of hyperkalemia
  • When renal function is normal, consider the following:
    • Hypoaldosteronism or renal tubular acidosis type 4 (particularly in the setting of marked volume depletion)
    • Medication effects. Examples include potassium-sparing diuretics (e.g., spironolactone), nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin inhibitors, trimethoprim, and cyclosporine.
    • Primary adrenal insufficiency or deficiency of an adrenal synthetic enzyme

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with pseudohypoaldosteronism type II (PHAII), the following evaluations are recommended:

  • Serum electrolyte analysis
  • Noninvasive blood pressure measurement
  • Medical genetics consultation

Treatment of Manifestations

Electrolyte and blood pressure abnormalities of PHAII are corrected with thiazide diuretics. Metabolic abnormalities and hypertension generally improve within one week.

Different thiazide diuretics exist, with different dosing regimens. In general dosing is titrated to normalization of blood pressure. It is possible that dosing may need to be increased over time or that additional anti-hypertensives may be required to adequately control blood pressure.

There are no established guidelines regarding age at which treatment should begin for individuals with PHAII, but affected children who have hypertension are generally treated.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Prevention of Secondary Complications

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

Surveillance

Appropriate surveillance includes routine electrolyte and blood pressure measurements, monitored in the same manner as for any patient treated with a thiazide diuretic.

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

Testing of first-degree relatives of individuals with PHAII is important to permit early diagnosis and treatment of other family members with the disorder. This can most readily be accomplished by measurement of serum potassium concentration and blood pressure. Genetic testing for the family-specific mutation (if known) can also be performed.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

During the pregnancy of a woman with PHAII, electrolytes and blood pressure should be monitored regularly and blood pressure medication adjusted as needed.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

All types of pseudohypoaldosteronism type II (PHAII) are inherited in an autosomal dominant manner. PHAIID may also be inherited in an autosomal recessive manner.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Many individuals diagnosed with PHAII have an affected parent.
  • A proband with PHAII may have the disorder as the result of a de novo mutation. Gong et al [2008] reported a de novo WNK4 mutation; the proportion of cases caused by de novo mutation is unknown.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, a de novo mutation in the proband is a possibility. Although no instances of germline mosaicism have been reported, it also remains a possibility. The incidence of germline mosaicism is unknown
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical evaluation (electrolyte analysis and blood pressure measurement) and/or molecular genetic testing for the disease-causing mutation present in the proband.
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome as a result of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although many individuals diagnosed with pseudohypoaldosteronism type II (PHAII) have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected or has a pathogenic variant, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for PHAII because of the possibility of reduced penetrance in a parent.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with PHAII has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a pathogenic variant, his or her family members may be at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive PHAIID are obligate heterozygotes (carriers) for a pathogenic variant in KLHL3.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like PHAII) do not affect intellect and have effective treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)
    Cystic Fibrosis / Pulmonary Research & Treatment Center
    7019 Thurston Bowles Building
    CB #7248
    Chapel Hill NC 27599-7248
    Fax: 919-966-7524; 919-843-5309
    Email: godwine@med.unc.edu; sminnix@med.unc.edu
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Pseudohypoaldosteronism Type II: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Pseudohypoaldosteronism Type II (View All in OMIM)

601844PROTEIN KINASE, LYSINE-DEFICIENT 4; WNK4
605232PROTEIN KINASE, LYSINE-DEFICIENT 1; WNK1
614491PSEUDOHYPOALDOSTERONISM, TYPE IIB; PHA2B
614492PSEUDOHYPOALDOSTERONISM, TYPE IIC; PHA2C

Molecular Genetic Pathogenesis

Mutations in the genes encoding two members of the WNK protein family of serine-threonine kinases, WNK1 and WNK4, have been implicated in the pathogenesis of pseudohypoaldosteronism type II (PHAII) [Wilson et al 2001]. Members of this kinase family are named WNK (or with no lysine [K]) kinases because of their unique substitution of cysteine for lysine at a highly conserved residue within the catalytic kinase domain [Xu et al 2000]. Over the past decade, members of the WNK kinase family have been shown to regulate the coordinated transport of Na+, K+, and Cl- ions across epithelia in a variety of tissues [Kahle et al 2008].

Alterations in WNK1 and WNK4 are present in only a minority of individuals with PHAII, motivating the search for additional genetic contributions to the disorder in other families. Recently, causative mutations in kelch-like 3 (KLHL3) and cullin 3 (CUL3) have been identified in the majority of families with PHAII [Boyden et al 2012, Louis-Dit-Picard et al 2012]. The protein products of KLHL3 and CUL3 function together as part of the cullin-RING E3 ubiquitin ligase complex, which has a role in ubiquitin-mediated protein degradation.

The electrolyte and blood pressure abnormalities in individuals with PHAII are readily corrected with thiazide diuretics, inhibitors of the Na-Cl cotransporter (NCC; encoded by SLC12A3) expressed in the renal distal convoluted and connecting tubules (see Management, Treatment of Manifestations). This clinical observation led to the initial hypothesis that increased activity of NCC could play a role in the pathogenesis of PHAII [Gordon 1986]. However, to date, no PHAII-causing mutations in the gene encoding NCC have been demonstrated.

WNK1

Gene structure. WNK1 transcript variant 1 (reference sequence NM_018979.3) has 30 exons and encodes the most common protein isoform. Alternatively spliced transcript variants have been described; the full-length nature of all of them has yet to be determined (www.ncbi.nlm.nih.gov/gene/65125). See Normal gene product. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Mutations in WNK1 have been reported in two families with PHAII [Wilson et al 2001]. Both mutations are large deletions (41 kb and 21 kb) that occur within the 60-kb intron 1 of WNK1. The deletions do not affect the coding sequence of the flanking exons.

Table 2. Selected WNK1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
g.18538_59810del 1p.(=) 2NG_007984​.2
g.28500_50277del 1 p.(=) 2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Deletions within intron 1

2. Indicates that no effect on protein level is expected

Normal gene product. WNK1 encodes at least four different alternatively spliced WNK1 transcripts (See Entrez Gene for further details). The interplay between these isoforms is complex. Two variants were initially identified: a longer isoform with ubiquitous tissue expression (L-WNK1) and a smaller isoform that lacks the 5’ kinase domain of the larger isoform and appears to be kidney-specific (KS-WNK1) [Delaloy et al 2003, O’Reilly et al 2003]. A neuronal isoform of WNK1 (termed WNK1/HSN2) that is highly expressed in the cell body of sensory ganglia neurons and neuronal projections has been identified. Mutations in an alternatively spliced exon of the transcript that encodes this isoform cause autosomal recessive hereditary sensory and autonomic neuropathy type 2, a disorder of progressive sensory deficit to touch, temperature, and pain [Shekarabi et al 2008].

In vitro studies in Xenopus oocytes and mammalian cells indicate that the mouse L-Wnk1 isoform inhibits the activity of mouse Wnk4 [Yang et al 2003]. As Wnk4 inhibits the activity of NCC (the Na-Cl cotransporter) encoded by SLC12A3, increased expression of L-Wnk1 is predicted to lead indirectly to increased activity of NCC [reviewed in Kahle et al 2008]. In addition, the KS-Wnk1 isoform decreases the activity of NCC by antagonizing the effect of L-Wnk1 in Xenopus [Subramanya et al 2006] and transgenic mice [Liu et al 2011].

As a multifunctional regulator of ion channels and transporters, WNK1 also inhibits the K+ channel ROMK1, encoded by KCNJ1 [Liu et al 2009] and (probably via phosphorylation of downstream kinase SGK-1) activates the amiloride-sensitive Na+ channel ENaC encoded by SCNN1A, SCNN1B, and SCNN1G [Xu et al 2005, Hadchouel et al 2010].

Abnormal gene product. Both of the known WNK1 deletions causing PHAII occur within the first intron of the gene and do not affect the amino acid structure of the gene product(s). It was initially shown that deletion within the first intron increases WNK1 transcription in peripheral leukocytes [Wilson et al 2001]. Subsequent work using a transgenic mouse model demonstrated that the intronic deletion leads to increased expression of both L-WNK1 and KS-WNK1 in the distal convoluted tubule and ectopic expression of KS-WNK1 in other tissues [Delaloy et al 2008]. This same group also generated a mouse model containing a heterozygous deletion of the endogenous first intron and found increased L-WNK1 expression in the distal convoluted tubule [Vidal-Petiot et al 2013]. These findings support the hypothesis that the deletion within the first intron leads to increased expression of L-WNK1, which should inhibit the activity of WNK4 and thus relieve suppression of the activity of NCC.

A knockout mouse model of L-WNK1 has also been generated, and mice with a heterozygous targeted disruption of the L-Wnk1 transcript have significantly decreased blood pressure compared to wild-type [Zambrowicz et al 2003]. Mice with targeted disruption of KS-Wnk1 exhibited increased activity of NCC, altered function of the ROMK (encoded by KCNJ1) and BKCa potassium channels, and decreased ENaC expression [Hadchouel et al 2010], confirming previous in vitro observations.

WNK4

Gene structure. WNK4 has 19 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. All reported mutations are missense alterations.

Table 3. Selected WNK4 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1679A>Gp.Glu560GlyNM_032387​.4
NP_115763​.2
c.1682C>Tp.Pro561Leu
c.1684G>Ap.Glu562Lys
c.1690G>Cp.Asp564His
c.1691A>Cp.Asp564Ala
c.1693C>Gp.Gln565Glu
c.3505A>Gp.Lys1169Glu
c.3553C>Tp.Arg1185Cys

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. WNK4 product is a 1243-amino acid protein encoded by a 3732-nucleotide open reading frame within a 4-kb cDNA transcript. Northern blot analysis showed expression primarily within the kidney, but immunofluorescence studies have shown the protein is present in the epithelial lining of a variety of tissues including the colon, liver, and pancreas [Kahle et al 2004a].

WNK4 has been shown to regulate the activity of a number of ion transporters through heterologous expression in Xenopus oocytes and in mammalian cell systems [Kahle et al 2008]. WNK4 inhibits the activity of NCC and ROMK in Xenopus oocytes [Kahle et al 2003, Wilson et al 2003, Yang et al 2003]. WNK4 has also been shown to increase paracellular chloride permeability in mammalian kidney cells via claudin phosphorylation [Kahle et al 2004b, Yamauchi et al 2004, Tatum et al 2007]. Like WNK1, WNK4 also regulates other structurally diverse but functionally related ion channels including ENaC [Ring et al 2007a, Ring et al 2007b] and the cation nonselective TRP channels TRPV4 and TRPV5 [Fu et al 2006].

Abnormal gene product. The effects of PHAII-associated WNK4 mutations on the above targets have been evaluated in vitro in oocytes and mammalian cells and in vivo in mouse models [reviewed in McCormick & Ellison 2011]. Initial experiments of heterologous expression in Xenopus oocytes focused on effects of WNK4 mutations on NCC activity. These studies showed that PHAII-associated WNK4 mutations decrease the inhibitory effect of WNK4 on NCC activity [Wilson et al 2003, Yang et al 2003]. Further studies showed that WNK4 mutations also lead to increased inhibition of ROMK in Xenopus and increased chloride permeability in MDCK (Madin-Darby canine kidney) cells compared to wild-type WNK4 [Kahle et al 2003, Kahle et al 2004a, Yamauchi et al 2004]. Together, these findings predict that WNK4 mutations in PHAII lead to increased tubular Na+ and Cl- resorption and decreased potassium secretion, consistent with the phenotype observed in persons with PHAII.

In vivo support of some of these early in vitro findings, along with other novel insights, came from the development and characterization of mouse models of PHAII [Lalioti et al 2006, Yang et al 2007]. Mice transgenic for a chromosomal segment encoding the murine Wnk4 with a Gln562Glu mutation (orthologous to the human p.Gln565Glu mutation) had hyperkalemia, higher blood pressure, and hypercalciuria compared to mice transgenic for a chromosomal segment encoding wild-type Wnk4 [Lalioti et al 2006]. In addition, marked hyperplasia of the distal convoluted tubule (DCT) and increased expression of NCC were noted in mutant Wnk4 transgenic mice but not in wild-type Wnk4 transgenic mice. All abnormalities were entirely corrected when mutant Wnk4 transgenic mice were crossed with mice harboring a targeted disruption of the gene encoding NCC, indicating that the effect of mutant Wnk4 on NCC activity alone is sufficient to cause the PHAII phenotype. Essentially similar findings were reported in a mouse Wnk4 mutant knock-in model of PHAII [Yang et al 2007].

Most PHAII-causing mutations in WNK4 cluster within a highly conserved non-catalytic domain just distal to the kinase domain. Recent in vitro studies have demonstrated that this segment is critical for binding to KLHL3, and PHAII-associated mutations within this domain disrupt interactions between WNK4 and KLHL3 [Ohta et al 2013, Shibata et al 2013, Wakabayashi et al 2013]. Due to the role of KLHL3 in ubiquitin-mediated proteolysis (discussed below), this should lead to increased WNK4 levels. Indeed, increased WNK4 levels are reported in the WNK4 mouse models of PHAII discussed above [Shibata et al 2013, Wakabayashi et al 2013].

It has also been suggested that mutations within this segment disrupt a calcium-sensing mechanism important in the regulation of WNK4 kinase activity [Na et al 2012]. Similarly, the PHAII-associated p.Arg1185Cys mutation (located near the C-terminus of WNK4 and separate from this domain) has also been implicated in impaired calcium-sensing and altered phosphorylation by SGK1 [Na et al 2013].

KLHL3

Gene structure. KLHL3 is widely expressed with at least three alternatively spliced isoforms reported. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Dominant KLHL3 alterations that cause PHAII are missense mutations that cluster in segments connecting beta-strands of Kelch propeller blades within the C-terminal Kelch propeller domain and disrupt substrate binding. Recessive KLHL3 alterations occur throughout the gene and include frameshift and premature termination mutations.

Normal gene product. KLHL3 is a component of the cullin-RING E3 ubiquitin ligase complex, which functions in ubiquitin-mediated proteolysis. KLHL3 contains an N-terminal bric-a-brac tramtrack broad complex (BTB) domain that has a role in binding to CUL3 and a BTB and C-terminal Kelch (BACK) domain. KLHL3 also contains a C-terminal six-bladed Kelch propeller domain that functions in substrate binding.

Wild-type KLHL3 has been shown to bind to WNK4 and WNK1 [Ohta et al 2013, Shibata et al 2013, Wakabayashi et al 2013]. Furthermore, binding of KLHL3 to WNK4 has been shown to result in ubiquitination and degradation of WNK4 in vitro, suggesting that KLHL3 normally regulates WNK4 levels via ubiquitin-mediated proteolysis [Shibata et al 2013, Wakabayashi et al 2013, Wu & Peng 2013]. Expression of KLHL3 together with binding of KLHL3 to WNK1 has also been shown to result in ubiquitination of WNK1 [Ohta et al 2013].

Immunostaining of mouse kidney demonstrates that KLHL3 is predominantly present in the distal convoluted tubule and collecting duct [Boyden et al 2012, Louis-Dit-Picard et al 2012].

Abnormal gene product. Missense mutations in KLHL3 that cause PHAII disrupt binding to WNK4, WNK1, or CUL3 and lead to decreased ubiquitination and increased levels of WNK4 [Mori et al 2013, Ohta et al 2013, Shibata et al 2013, Wakabayashi et al 2013]. Mutant KLHL3 has also been shown to decrease WNK4-mediated clearance of ROMK from the cell membrane [Shibata et al 2013].

CUL3

Gene structure. CUL3 is widely expressed and has several alternatively spliced isoforms. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. CUL3 alterations causing PHAII occur within intron 8, exon 9, or intron 9 and disrupt splicing of exon 9. This results in a 57-amino acid in-frame deletion.

Normal gene product. CUL3 is a component of the cullin-RING E3 ubiquitin ligase complex, which functions in ubiquitin-mediated proteolysis. Immunostaining of mouse kidney demonstrates that CUL3 is present throughout the nephron [Boyden et al 2012].

Abnormal gene product. It has been suggested that CUL3 mutations in PHAII may disrupt ubiquitination of at least a subset of KLHL3 targets [Boyden et al 2012]. The observation that all reported CUL3 mutations impair splicing of exon 9 and result in an in-frame deletion of a segment of CUL3 may hint at the functional specificity of these mutations [Boyden et al 2012].

References

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Suggested Reading

  1. Brooks AM, Owens M, Sayer JA, Salzmann M, Ellard S, Vaidya B. Pseudohypoaldosteronism type 2 presenting with hypertension and hyperkalaemia due to a novel mutation in the WNK4 gene. QJM. 2012;105:791–4. [PubMed: 21764813]
  2. Golbang AP, Murthy M, Hamad A, Liu CH, Cope G, Van’t Hoff W, Cuthbert A, O’Shaughnessy KM. A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene. Hypertension. 2005;46:295–300. [PubMed: 15998707]
  3. Zhang C, Wang Z, Xie J, Yan F, Wang W, Feng X, Zhang W, Chen N. Identification of a novel WNK4 mutation in Chinese patients with pseudohypoaldosteronism type II. Nephron Physiol. 2011;118:53–61. [PubMed: 21196779]

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Revision History

  • 16 January 2014 (me) Comprehensive update posted live
  • 10 November 2011 (me) Review posted live
  • 25 April 2011 (ktk) Original submission
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