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Pseudohypoaldosteronism Type II

Synonyms: Familial Hyperkalemic Hypertension, Gordon's Syndrome, PHAII

, MD.

Author Information

Initial Posting: ; Last Update: February 16, 2017.

Estimated reading time: 24 minutes

Summary

Clinical characteristics.

Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension. 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 of PHAII is established in a proband:

  • With hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels;
    AND/OR
  • By the identification of a heterozygous pathogenic variant in CUL3, WNK1, or WNK4 or a heterozygous pathogenic variant or biallelic pathogenic variants in KLHL3.

Management.

Treatment of manifestations: Electrolyte and blood pressure abnormalities of PHAII in children and adults are often 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.

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: 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 .

Pregnancy management: Affected pregnant women should undergo routine monitoring of electrolytes and blood pressure, with adjustments to antihypertensive medication dosage as needed. 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.

Genetic counseling.

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. Many pathogenic variants in CUL3 arise de novo and are not inherited from a parent. Each child of an individual with autosomal dominant PHAII has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant(s) in the family is known.

Diagnosis

No formal diagnostic criteria for PHAII have been published.

Suggestive Findings

Pseudohypoaldosteronism type II (PHAII) should be suspected in individuals with the following clinical features, supportive laboratory findings, and family history.

Clinical features. Hypertension (blood pressure >140/90 mm Hg) generally manifesting in adolescence or adulthood but also reported in children. Note: The absence of frank hypertension does not preclude the diagnosis.

Supportive laboratory findings

  • Hyperkalemia in the absence of impaired glomerular filtration
    • Serum concentration of potassium ranges from mildly (serum K ~5.0-6.0 mmol/L) to severely elevated (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L).
    • This finding is nearly universal in affected individuals at all ages.
  • Metabolic acidosis: serum concentration of bicarbonate ranging from 14 to 24 mmol/L (normal range: ~22-29 mmol/L)
  • Hyperchloremia: serum concentration of chloride ranging from 105 to 117 mmol/L (normal range: ~99-108 mmol/L)
  • Suppressed plasma renin levels
  • Variable serum aldosterone levels that tend to be relatively suppressed in the context of hyperkalemia
  • Serum calcium and parathyroid hormone levels that are normal. However, hypercalciuria is noted in at least a subset of individuals.

Family history. A first-degree relative with similar findings. Note: Absence of a family history of a first-degree relative with similar findings does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of PHAII is established in a proband with hyperkalemia (in the setting of normal glomerular filtration) often accompanied by hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels and/or by the identification of a heterozygous pathogenic variant in CUL3, KLHL3, WNK1, or WNK4 or biallelic pathogenic variants in KLHL3 (see Table 1). Note: PHAII is sometimes referred to by a subtype designation based on the associated gene; see Nomenclature.

Molecular genetic testing approaches can include serial single-gene testing and use of a multigene panel.

Serial single-gene testing

A multigene panel that includes CUL3, KLHL3, WNK1, and WNK4 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Pseudohypoaldosteronism Type II

Gene 1Proportion of PHAII Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detectable by This Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
CUL325/86 families reportedAll reported cases to dateNone reported
KLHL341/86 families reported 5Autosomal dominant: 29/86
Autosomal recessive: 12/86
Unknown 6
WNK18/86 families reportedSee footnote 72/2 8
WNK48/86 families reportedAll reported cases to dateNone reported
Unknown 94/52 10NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

7.

Recently, six kindreds (9 individuals) were reported in preliminary results to have pathogenic missense variants in WNK1 (detailed in Molecular Genetics).

8.

Two large deletions have been reported (see Molecular Genetics) [Wilson et al 2001].

9.

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

10.

Denominator is from the only report to document the number of PHAII individuals who did not have variants in CUL3, KLHL3, WNK1, or WNK4 [Boyden et al 2012].

Clinical Characteristics

Clinical Description

Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension. More than 180 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].

Phenotype Correlations by Gene

Individuals with a heterozygous CUL3 pathogenic variant tend to have more severe hyperkalemia and metabolic acidosis, earlier development of hypertension, and greater likelihood of growth impairment compared to those harboring KLHL3, WNK1, or WNK4 alterations [Boyden et al 2012].

In general, clinical manifestations of PHAII appear to be milder in individuals with a heterozygous WNK1 or WNK4 pathogenic variant compared to those with a heterozygous CUL3 or a heterozygous or biallelic KLHL3 pathogenic variant(s) [Boyden et al 2012].

Individuals with biallelic KLHL3 pathogenic variants may have a more severe phenotype than individuals with a heterozygous pathogenic variant in KLHL3 [Boyden et al 2012, Louis-Dit-Picard et al 2012].

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).

Therefore, the term "pseudohypoaldosteronism" is a misnomer in the context of PHAII, as affected individuals have hyperkalemia with hypertension (instead of volume depletion). Some authorities prefer the descriptive name familial hyperkalemic hypertension (FHHt) for this reason.

PHAII is sometimes referred to by a subtype designation based on the associated gene, as follows:

  • PHA type IIA (PHA2A): Unknown genetic cause (see Table 1, footnotes 9 and 10)
  • PHA type IIB (PHA2B): WNK4
  • PHA type IIC (PHA2C): WNK1
  • PHA type IIE (PHA2E): CUL3
  • PHA type IID (PHA2D): KLHL3

Prevalence

The prevalence of the disorder is unknown. To date more than 180 individuals and families with PHAII have been reported.

Differential Diagnosis

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:

  • Chronic kidney disease, especially when secondary to diabetes, is the most commonly identified cause of hyperkalemia.
  • When renal function is normal, consider the following:
    • Hypoaldosteronism or acquired 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

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, if not performed as part of the diagnostic evaluation:

  • Serum electrolyte analysis
  • Noninvasive blood pressure measurement
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Electrolyte and blood pressure abnormalities of PHAII are often 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 will need to be increased over time or that additional anti-hypertensives will 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 person 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

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Evaluations can include:

  • Measurement of serum potassium concentration and blood pressure;
  • Molecular genetic testing if the pathogenic variant(s) in the family are known.

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.

Some antihypertensive medications (including thiazide diuretics) have been associated with adverse fetal outcome, especially when taken during the first trimester of pregnancy. The best time to discuss the risk to the fetus associated with a maternal medication is prior to conception. Women with PHAII who become pregnant should be referred to an obstetrics group with expertise in high-risk pregnancies.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe 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

Pseudohypoaldosteronism type II (PHAII) is most commonly inherited in an autosomal dominant manner. PHAIID can 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 pathogenic variant [Gong et al 2008].
    Fifteen of 182 reported cases have been de novo; 14/15 caused by a heterozygous pathogenic CUL3 variant and 1/15 caused by a heterozygous KLHL3 pathogenic variant [Boyden et al 2012, Tsuji et al 2013, Picard et al 2015a].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include clinical evaluation (electrolyte analysis and blood pressure measurement) and/or molecular genetic testing if a CUL3, KLHL3, WNK1, or WNK4 pathogenic variant has been identified in the proband.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (although no instances of germline mosaicism have been reported, it remains a possibility).
  • 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, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

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 slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with PHAII has a 50% chance of inheriting the CUL3, KLHL3, WNK1, or WNK4 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 KLHL3 pathogenic variant).
  • Carriers of a KLHL3 pathogenic variant associated with autosomal recessive PHAIID are typically asymptomatic and do not appear to be at risk of developing the disorder; however, thorough clinical analysis of such individuals over time has not been reported.

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.
  • Carriers of a KLHL3 pathogenic variant associated with autosomal recessive PHAIID are typically asymptomatic and are not thought to be at risk of developing the disorder.

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 of a KLHL3 pathogenic variant.

Carrier (heterozygote) detection. Carrier testing for at-risk relatives requires prior identification of the KLHL3 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 pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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 and Preimplantation Genetic Diagnosis

Once the CUL3, KLHL3, WNK1, or WNK4 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for PHAII are possible.

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. While decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate.

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
    Marsico Lung Institute
    7215 Marsico Hall
    CB #7248
    Chapel Hill NC 27599-7248
    Fax: 919-966-7524; 919-843-5309
    Email: godwine@med.unc.edu; kelli_sullivan@med.unc.edu
  • Metabolic Support UK
    5 Hilliards Court, Sandpiper Way
    Chester Business Park
    Chester CH4 9QP
    United Kingdom
    Phone: 0845 241 2173
    Email: contact@metabolicsupportuk.org

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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Pseudohypoaldosteronism Type II (View All in OMIM)

145260PSEUDOHYPOALDOSTERONISM, TYPE IIA; PHA2A
601844PROTEIN KINASE, LYSINE-DEFICIENT 4; WNK4
603136CULLIN 3; CUL3
605232PROTEIN KINASE, LYSINE-DEFICIENT 1; WNK1
605775KELCH-LIKE 3; KLHL3
614491PSEUDOHYPOALDOSTERONISM, TYPE IIB; PHA2B
614492PSEUDOHYPOALDOSTERONISM, TYPE IIC; PHA2C
614495PSEUDOHYPOALDOSTERONISM, TYPE IID; PHA2D
614496PSEUDOHYPOALDOSTERONISM, TYPE IIE; PHA2E

Molecular Genetic Pathogenesis

Pathogenic variants 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, pathogenic variants 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 CUL3 and KLHL3 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 variants in the gene encoding NCC have been demonstrated.

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.

Pathogenic 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 pathogenic variants in PHAII may disrupt ubiquitination of at least a subset of KLHL3 targets [Boyden et al 2012]. The observation that all reported CUL3 pathogenic variants 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 pathogenic variants [Boyden et al 2012].

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.

Pathogenic variants. Dominant KLHL3 pathogenic variants that cause PHAII are missense alternations that cluster in segments connecting beta-strands of Kelch propeller blades within the C-terminal Kelch propeller domain and disrupt substrate binding.

Recessive KLHL3 pathogenic variants occur throughout the gene and include frameshift and premature termination variants.

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 variants 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]. Mutated KLHL3 has also been shown to decrease WNK4-mediated clearance of ROMK from the cell membrane [Shibata et al 2013].

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. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic variants in WNK1 were initially reported in two families with PHAII [Wilson et al 2001]. Both 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. Recently, 6 kindreds (9 individuals) were reported to have pathogenic missense variants in WNK1, coupled with a phenotype that includes hyperkalemia and acidosis; the hypertension was minimal. The pathogenic missense variants clustered in the region homologous to the acidic domain mutated in WNK4 [Picard et al 2015b].

Table 2.

Selected WNK1 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
g.18538_59810del 1,2See footnote 3NG_007984​.2
g.28500_50277del 2See footnote 3

Note on variant classification: Variants listed in the table have been provided by the author. 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Deletion within intron 1 (also known as NG_007984.2:c.759+12272_760-5774del)

2.
3.

No amino acid change is expected.

Normal gene product. WNK1 encodes at least four different alternatively spliced WNK1 transcripts (See see Table A, Gene 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. Pathogenic variants 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].

The L-Wnk1 isoform can activate the kinase SPAK (encoded by STK39), which in turn can phosphorylate and activate NCC (the Na-Cl cotransporter) encoded by SLC12A3. The KS-WNK1 isoform, expressed predominantly along the distal nephron, binds to and inhibits the activity of L-Wnk1 in Xenopus [Subramanya et al 2006] and transgenic mice [Liu et al 2011]. WNK1 can also interact, through a conserved "HQ" domain, with other WNK kinases, including WNK4. These interactions have complex functional effects [Yang et al 2003, Chávez-Canales et al 2014].

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 demonstrated that the intron deletion leads to 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 phosphorylate and stimulate 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.

Pathogenic variants. All reported pathogenic variants are missense alterations. All pathogenic variants reported to date have been identified in exons 7 and 17 [Wilson et al 2001, Golbang et al 2005, Brooks et al 2012].

Table 3.

Selected WNK4 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. WNK4 product is a 1,243-amino acid protein encoded by a 3,732-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]. The major effect of WNK4 in vivo appears to be stimulation of NCC; it may also inhibit ROMK [Kahle et al 2003, Wilson et al 2003]. WNK4 has also been reported 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]. Deletion of WNK4 results in a phenotype that resembles Gitelman syndrome, indicating that the predominant WNK4 effect in vivo is stimulation of NCC [Castañeda-Bueno et al 2012, Takahashi et al 2014].

Abnormal gene product. The effects of PHAII-associated WNK4 pathogenic variants on the above targets have been evaluated in vitro in oocytes and mammalian cells and in vivo in mouse models [reviewed in Chávez-Canales et al 2014].

Important information about the mechanisms underlying WNK4-related PHAII 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 pathogenic variant (orthologous to the human p.Gln565Glu pathogenic variant) 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 mutated Wnk4 transgenic mice but not in wild type Wnk4 transgenic mice. All abnormalities were entirely corrected when mutated Wnk4 transgenic mice were crossed with mice harboring a targeted disruption of the gene encoding NCC, indicating that the effect of mutated Wnk4 on NCC activity alone is sufficient to cause the PHAII phenotype. Essentially similar findings were reported in a mouse Wnk4 mutated knock-in model of PHAII [Yang et al 2007].

Most PHAII-causing variants 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 variants 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 (see KLHL3), 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 pathogenic variants 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 pathogenic variant (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].

References

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Chapter Notes

Author History

David H Ellison, MD (2017-present)
Kristopher T Kahle, MD, PhD; Harvard Medical School (2011-2017)
Frederick H Wilson, MD, PhD; Harvard Medical School (2011-2017)

Revision History

  • 16 February 2017 (ma) Comprehensive update posted live
  • 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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