Pseudohypoaldosteronism type 2 (PHA2) is caused by problems that affect regulation of the amount of sodium and potassium in the body. Sodium and potassium are important in the control of blood pressure, and their regulation occurs primarily in the kidneys.

People with PHA2 have high blood pressure (hypertension) and high levels of potassium in their blood (hyperkalemia) despite having normal kidney function. The age of onset of PHA2 is variable and difficult to pinpoint; some affected individuals are diagnosed in infancy or childhood, and others are diagnosed in adulthood. Hyperkalemia usually occurs first, and hypertension develops later in life. Affected individuals also have high levels of chloride (hyperchloremia) and acid (metabolic acidosis) in their blood (together, referred to as hyperchloremic metabolic acidosis). People with hyperkalemia, hyperchloremia, and metabolic acidosis can have nonspecific symptoms like nausea, vomiting, extreme tiredness (fatigue), and muscle weakness. People with PHA2 may also have high levels of calcium in their urine (hypercalciuria).

PHA2 can be caused by mutations in the WNK1, WNK4, CUL3, or KLHL3 gene. These genes play a role in the regulation of blood pressure.

The proteins produced from the WNK1 and WNK4 genes help control the amount of sodium and potassium in the body by regulating channels in the cell membrane that control the transport of sodium or potassium into and out of cells. This process primarily occurs in the kidneys. Mutations in either of these genes disrupt control of these channels, leading to abnormal levels of sodium and potassium in the body. As a result, affected individuals develop hypertension and hyperkalemia.

The proteins produced from the CUL3 gene (called cullin-3) and the KLHL3 gene help control the amount of WNK1 and WNK4 protein available. Cullin-3 and KLHL3 are two pieces of a complex, called an E3 ubiquitin ligase, that tags certain other proteins with molecules called ubiquitin. This molecule acts as a signal for the tagged protein to be broken down when it is no longer needed. E3 ubiquitin ligases containing cullin-3 and KLHL3 are able to tag the WNK1 and WNK4 proteins with ubiquitin, leading to their breakdown. Mutations in either the CUL3 or KLHL3 gene impair breakdown of the WNK4 protein. (The effect of these mutations on the WNK1 protein is unclear.) An excess of WNK4 likely disrupts control of sodium and potassium levels, resulting in hypertension and hyperkalemia.

Normal Function

The CUL3 gene provides instructions for making a protein called cullin-3. This protein plays a role in the ubiquitin-proteasome system, which breaks down (degrades) unwanted proteins inside cells.

The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. Cullin-3 is a core piece of a complex known as an E3 ubiquitin ligase. E3 ubiquitin ligases tag proteins with molecules called ubiquitin. Ubiquitin signals specialized cell structures known as proteasomes to attach (bind) to the tagged proteins and degrade them. The ubiquitin-proteasome system also regulates several critical cell activities by controlling the amounts of proteins involved in them.

E3 ubiquitin ligases that contain cullin-3 tag many proteins that perform a variety of functions, such as cell growth and division. These ligases also tag blood pressure-related proteins called WNK1 and WNK4, which are produced from the WNK1 and WNK4 genes. By regulating the amount of WNK1 and WNK4 available, cullin-3 plays a role in blood pressure control.

Health Conditions Related to Genetic Changes

CUL3-related neurodevelopmental disorder

CUL3 gene variants (also called mutations) can cause a condition called CUL3-related neurodevelopmental disorder. This condition affects neurological and physical development.

The CUL3 gene variants that cause CUL3-related neurodevelopmental disorder can lead to the production of nonfunctional cullin-3 proteins, and in some cases, no cullin-3 protein production at all. Without the normal amount of functioning cullin-3 proteins, the breakdown of unwanted proteins by the ubiquitin-proteasome system becomes impaired at key developmental stages. As a result, unnecessary proteins build up and interfere with the normal function of cells. Since cullin-3 is produced in nerve cells throughout the brain, it is likely that the protein's dysfunction damages nerve cells, causing many of the signs and symptoms of CUL3-related neurodevelopmental disorder.

Researchers suspect that each variant that causes CUL3-related neurodevelopmental disorder affects the tagging of specific proteins by the E3 ubiquitin ligase complex. So, each variant could interfere with the breakdown of proteins differently. This mechanism may explain the variety of signs and symptoms seen in individuals with CUL3-related neurodevelopmental disorder.

Pseudohypoaldosteronism type 2

Specific variants in a particular region of the CUL3 gene can cause pseudohypoaldosteronism type 2 (PHA2), a condition characterized by high blood pressure (hypertension) and high levels of potassium in the blood (hyperkalemia). These variants lead to the production of an abnormally short cullin-3 protein that is missing a particular region.

Studies show that this change alters the function of the E3 ubiquitin ligase complex. It impairs the breakdown of the WNK4 protein, although the exact mechanism is unclear. The resulting excess of WNK4 protein disrupts normal control of blood pressure, causing hypertension and other features of PHA2. While PHA2 and CUL3-related neurodevelopmental disorder share a genetic cause, the features of PHA2 do not overlap with the neurological or physical problems of CUL3-related neurodevelopmental disorder.

It is unknown if the breakdown of WNK1 is affected by the alterations to E3 ubiquitin ligase or whether WNK1 plays a role in cases of PHA2 caused by CUL3 gene variants.

Other Names for This Gene

• CUL-3
• cullin-3 isoform 1
• cullin-3 isoform 2
• cullin-3 isoform 3
• PHA2E

Genomic Location

Normal Function

The KLHL3 gene provides instructions for making a protein that plays a role in the cell machinery that breaks down (degrades) unwanted proteins, called the ubiquitin-proteasome system.

The KLHL3 protein is one piece of a complex known as an E3 ubiquitin ligase. E3 ubiquitin ligases function as part of the ubiquitin-proteasome system by tagging damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to specialized cell structures known as proteasomes, which attach (bind) to the tagged proteins and degrade them. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the level of proteins involved in several critical cell activities such as the timing of cell division and growth.

The KLHL3 protein identifies the target of the E3 ubiquitin ligase complex and attaches the complex to it. Complexes containing the KLHL3 protein tag proteins called WNK1 and WNK4 with ubiquitin. The WNK1 and WNK4 proteins are involved in controlling blood pressure in the body. By regulating the amount of these proteins available, KLHL3 plays a role in blood pressure control.

Health Conditions Related to Genetic Changes

Pseudohypoaldosteronism type 2

At least 36 KLHL3 gene mutations have been found to cause pseudohypoaldosteronism type 2 (PHA2), a condition characterized by high blood pressure (hypertension) and high levels of potassium in the blood (hyperkalemia). These mutations alter the KLHL3 protein, impairing its ability to attach to the E3 ubiquitin ligase complex or to WNK4. As a result, the complex is unable to tag WNK4 with ubiquitin, and degradation of the protein is impaired. An excess of WNK4 disrupts normal control of blood pressure, leading to hypertension and the other features of PHA2. It is unknown if WNK1 is affected by the abnormal E3 ubiquitin ligase complex or whether WNK1 plays a role in development of PHA2 caused by KLHL3 gene mutations.

Other Names for This Gene

• kelch-like family member 3
• kelch-like protein 3 isoform 1
• kelch-like protein 3 isoform 2
• kelch-like protein 3 isoform 3
• KIAA1129
• PHA2D

Genomic Location

Normal Function

The WNK1 gene provides instructions for making multiple versions (isoforms) of the WNK1 protein. The different WNK1 isoforms are important in several functions in the body, including blood pressure regulation and pain sensation.

One isoform produced from the WNK1 gene is the full-length version, called the L-WNK1 protein, which is found in cells throughout the body. A different isoform, called the kidney-specific WNK1 protein or KS-WNK1, is found only in kidney cells. The L-WNK1 and KS-WNK1 proteins act as kinases, which are enzymes that change the activity of other proteins by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions.

The L-WNK1 and KS-WNK1 proteins regulate channels in the cell membrane that control the transport of sodium or potassium into and out of cells. In the kidneys, sodium channels help transport sodium into specialized cells, which then transfer it into the blood. This transfer helps keep sodium in the body through a process called reabsorption. Potassium channels handle excess potassium that has been transferred from the blood into kidney cells. The channels transport potassium out of the cells in a process called secretion, so that it can be removed from the body in urine.

The L-WNK1 protein increases sodium reabsorption and decreases potassium secretion, whereas the KS-WNK1 protein has the opposite effect. Sodium and potassium are important for regulating blood pressure, and a balance of L-WNK1 protein and KS-WNK1 protein in the kidneys helps maintain the correct levels of sodium and potassium for healthy blood pressure.

Another isoform produced from the WNK1 gene, called the WNK1/HSN2 protein, is found in the cells of the nervous system, including nerve cells that transmit the sensations of pain, temperature, and touch (sensory neurons). The WNK1/HSN2 protein appears to regulate channels in the cell membrane that can transport negatively charged chlorine atoms (chloride ions). These channels maintain the proper amount of chloride inside cells, which is important for controlling the activation (excitation) of the neurons.

Health Conditions Related to Genetic Changes

Hereditary sensory and autonomic neuropathy type II

Mutations in the WNK1 gene are responsible for one type of hereditary sensory and autonomic neuropathy type II (HSAN2) called HSAN2A. People with HSAN2A lose the ability to feel pain or sense hot and cold. More than a dozen mutations in the WNK1 gene have been identified in people with HSAN2A. All of these mutations lead to an abnormally shortened WNK1/HSN2 protein that is probably nonfunctional. People with HSAN2A have a reduction in the number of sensory neurons; however, the role that the abnormal WNK1/HSN2 protein plays in that loss is unclear. The loss of sensory neurons results in the signs and symptoms of HSAN2A.

WNK1 gene mutations involved in HSAN2A do not appear to affect the L-WNK1 or KS-WNK1 isoforms.

Pseudohypoaldosteronism type 2

At least two mutations in the WNK1 gene have been found to cause pseudohypoaldosteronism type 2 (PHA2), a condition characterized by high blood pressure (hypertension) and high levels of potassium in the blood (hyperkalemia). The mutations involved in this condition delete large numbers of DNA building blocks (nucleotides) from the WNK1 gene. These deletions lead to increased activity of the WNK1 gene and excess L-WNK1 protein. An increase in L-WNK1 protein abnormally increases sodium reabsorption and blocks potassium secretion, resulting in hypertension and hyperkalemia.

WNK1 gene mutations involved in PHA2 do not appear to affect the KS-WNK1 or WNK1/HSN2 isoforms.

Other disorders

Studies have associated normal variations in the WNK1 gene with an increased risk of high blood pressure (hypertension) in people without PHA2 (described above). A combination of genetic variations and environmental factors likely influence the development of this complex condition.

Other Names for This Gene

• HSAN2
• HSN2
• KDP
• p65
• PPP1R167
• PRKWNK1
• prostate-derived sterile 20-like kinase
• protein kinase with no lysine 1
• protein kinase, lysine deficient 1
• PSK
• serine/threonine-protein kinase WNK1
• WNK1_HUMAN

Genomic Location

Normal Function

The WNK4 gene provides instructions for making a protein that plays a role in blood pressure regulation by helping control the amount of sodium and potassium in the body. The WNK4 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions.

The WNK4 protein regulates channels in the cell membrane that control the transport of sodium or potassium into and out of cells, which occurs primarily in the kidneys. Sodium channels help transport sodium into specialized kidney cells, which then transfer it into the blood. This transfer helps keep sodium in the body through a process called reabsorption. Potassium channels handle excess potassium that has been transferred from the blood into the kidney cells. The channels transport the potassium out of the cells in a process called secretion, so that it can be removed from the body in the urine. The WNK4 protein is able to promote sodium reabsorption and block potassium secretion. Depending on conditions in the cell, the WNK4 protein is also able to block (inhibit) sodium reabsorption.

Health Conditions Related to Genetic Changes

Pseudohypoaldosteronism type 2

At least eight mutations in the WNK4 gene have been found to cause pseudohypoaldosteronism type 2 (PHA2), a condition characterized by high blood pressure (hypertension) and high levels of potassium in the blood (hyperkalemia). The mutations involved in this condition change single protein building blocks (amino acids) in the WNK4 protein. The alterations to the WNK4 protein impair its breakdown, resulting in higher than normal levels of WNK4 protein and elevated WNK4 activity. The increase in WNK4 activity leads to increased sodium reabsorption and reduced potassium secretion, resulting in hypertension and hyperkalemia.

Other disorders

Studies have associated normal variations in the WNK4 gene with an increased risk of high blood pressure (hypertension) in people without pseudohypoaldosteronism type 2. A combination of genetic variations and environmental factors likely influence the development of this complex condition.

Other Names for This Gene

• PHA2B
• PRKWNK4
• protein kinase lysine-deficient 4
• protein kinase with no lysine 4
• serine/threonine-protein kinase WNK4
• WNK4_HUMAN

Genomic Location

This condition is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases caused by mutations in the WNK1, WNK4, or KLHL3 gene, an affected person inherits the mutation from one affected parent. While some cases caused by CUL3 gene mutations can be inherited from an affected parent, many result from new mutations in the gene and occur in people with no history of the disorder in their family.

Some cases caused by mutations in the KLHL3 gene are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

PHA2 is a rare condition; however, the prevalence is unknown.