Pseudohypoaldosteronism type 1 (PHA1) is a condition characterized by problems regulating the amount of sodium in the body. Sodium regulation, which is important for blood pressure and fluid balance, primarily occurs in the kidneys. However, sodium can also be removed from the body through other tissues, such as the sweat glands and colon. Pseudohypoaldosteronism type 1 is named for its characteristic signs and symptoms, which mimic (pseudo) low levels (hypo) of a hormone called aldosterone that helps regulate sodium levels. However, people with PHA1 have high levels of aldosterone.

There are two types of PHA1 distinguished by their severity, the genes involved, and how they are inherited. One type, called autosomal dominant PHA1 (also known as renal PHA1) is characterized by excessive sodium loss from the kidneys. This form of the condition is relatively mild and often improves in early childhood. The other type, called autosomal recessive PHA1 (also known as generalized or systemic PHA1) is characterized by sodium loss from the kidneys and other organs, including the sweat glands, salivary glands, and colon. This type of PHA1 is more severe and does not improve with age.

The earliest signs of both types of PHA1 are usually the inability to gain weight and grow at the expected rate (failure to thrive) and dehydration, which are typically seen in infants. The characteristic features of both types of PHA1 are excessive amounts of sodium released in the urine (salt wasting), which leads to low levels of sodium in the blood (hyponatremia), and high levels of potassium in the blood (hyperkalemia). Infants with PHA1 can also have high levels of acid in the blood (metabolic acidosis). Hyponatremia, hyperkalemia, or metabolic acidosis can cause nonspecific symptoms such as nausea, vomiting, extreme tiredness (fatigue), and muscle weakness in infants with PHA1.

Infants with autosomal recessive PHA1 can have additional signs and symptoms due to the involvement of multiple organs. Affected individuals may experience episodes of abnormal heartbeat (cardiac arrhythmia) or shock because of the imbalance of salts in the body. They may also have recurrent lung infections or lesions on the skin. Although adults with autosomal recessive PHA1 can have repeated episodes of salt wasting, they do not usually have other signs and symptoms of the condition.

Mutations in one of four different genes involved in sodium regulation cause autosomal dominant or autosomal recessive PHA1. Mutations in the NR3C2 gene cause autosomal dominant PHA1. This gene provides instructions for making the mineralocorticoid receptor protein. Mutations in the SCNN1A, SCNN1B, or SCNN1G genes cause autosomal recessive PHA1. Each of these three genes provides instructions for making one of the pieces (subunits) of a protein complex called the epithelial sodium channel (ENaC).

The mineralocorticoid receptor regulates specialized proteins in the cell membrane that control the transport of sodium or potassium into cells. In response to signals that sodium levels are low, such as the presence of the hormone aldosterone, the mineralocorticoid receptor increases the number and activity of these proteins at the cell membrane of certain kidney cells. One of these proteins is ENaC, which transports sodium into the cell; another protein simultaneously transports sodium out of the cell and potassium into the cell. These proteins help keep sodium in the body through a process called reabsorption and remove potassium from the body through a process called secretion.

Mutations in the NR3C2 gene lead to a nonfunctional or abnormally functioning mineralocorticoid receptor protein that cannot properly regulate the specialized proteins that transport sodium and potassium. As a result, sodium reabsorption and potassium secretion are both decreased, causing hyponatremia and hyperkalemia.

Mutations in the SCNN1A, SCNN1B, and SCNN1G genes result in reduced functioning or nonfunctioning ENaC channels. As in autosomal dominant PHA1, the reduction or absence of ENaC function in the kidneys leads to hyponatremia and hyperkalemia. In addition, nonfunctional ENaC channels in other body systems lead to additional signs and symptoms of autosomal recessive PHA1, including lung infections and skin lesions.

Normal Function

The NR3C2 gene provides instructions for making a protein called the mineralocorticoid receptor. This protein is important in regulating the amount of sodium in the body. Sodium regulation plays a role in blood pressure control and fluid balance. Certain hormones called mineralocorticoids attach (bind) to and turn on (activate) the mineralocorticoid receptor. Aldosterone is one mineralocorticoid that activates the mineralocorticoid receptor. The activated mineralocorticoid receptor acts as a transcription factor, which is a protein that binds to specific regions of DNA and helps control the activity (transcription) of particular genes.

The mineralocorticoid receptor regulates specialized proteins in the cell membrane that control the transport of sodium or potassium into cells. In response to signals that sodium levels in the body are low, the mineralocorticoid receptor increases the number and activity of these proteins at the cell membrane, especially in certain kidney cells. One of these proteins transports sodium into the cell, while another protein simultaneously transports sodium out of the cell and potassium into the cell. These proteins help keep sodium in the body through a process called reabsorption and remove potassium from the body through a process called secretion.

Health Conditions Related to Genetic Changes

Pseudohypoaldosteronism type 1

More than 50 mutations in the NR3C2 gene have been identified in people with pseudohypoaldosteronism type 1 (PHA1), a condition that typically begins in infancy and is characterized by low levels of sodium (hyponatremia) and high levels of potassium (hyperkalemia) in the blood. In particular, NR3C2 gene mutations are involved in autosomal dominant PHA1, a relatively mild form of the condition that can improve in childhood.

Mutations in the NR3C2 gene lead to a nonfunctional or abnormally functioning mineralocorticoid receptor protein that cannot properly regulate the specialized proteins that transport sodium and potassium. As a result, sodium reabsorption and potassium secretion are both decreased, causing hyponatremia and hyperkalemia.

Other disorders

One particular mutation in the NR3C2 gene can cause early-onset hypertension with severe exacerbation in pregnancy. People with this condition develop high blood pressure (hypertension) at an early age. The condition can affect males or females, and hypertension worsens in pregnant females.

The mutation involved in this condition changes one protein building block (amino acid) in the mineralocorticoid receptor protein. The amino acid serine is replaced with the amino acid leucine at position 810 in the protein (written as Ser810Leu or S810L). This mutation changes the shape of the receptor, which allows the receptor to be abnormally activated by non-mineralocorticoid hormones such as progesterone and cortisol. The increased mineralocorticoid receptor activity causes excessive sodium reabsorption, which leads to hypertension. Progesterone levels are elevated during pregnancy, which is why the condition worsens in pregnant females.

Other Names for This Gene

• aldosterone receptor
• FLJ41052
• MCR
• MCR_HUMAN
• MGC133092
• mineralocorticoid receptor
• mineralocorticoid receptor 1
• mineralocorticoid receptor delta
• MLR
• MR
• NR3C2VIT
• nuclear receptor subfamily 3, group C, member 2

Genomic Location

Normal Function

The SCNN1A gene provides instructions for making one piece, the alpha subunit, of a protein complex called the epithelial sodium channel (ENaC). The channel is composed of alpha, beta, and gamma subunits, each of which is produced from a different gene. These channels are found at the surface of certain cells called epithelial cells in many tissues of the body, including the kidneys, lungs, and sweat glands. The ENaC channel transports sodium into cells.

In the kidney, ENaC channels take sodium into cells in response to signals that sodium levels in the body are too low. From the kidney cells, this sodium is returned to the bloodstream rather than being removed from the body (a process called reabsorption). In addition to regulating the amount of sodium in the body, the flow of sodium ions helps control the movement of water in tissues. For example, ENaC channels in lung cells help regulate the amount of fluid in the lungs.

Health Conditions Related to Genetic Changes

Pseudohypoaldosteronism type 1

At least a dozen mutations in the SCNN1A gene cause pseudohypoaldosteronism type 1 (PHA1). This condition typically begins in infancy and is characterized by low levels of sodium (hyponatremia) and high levels of potassium (hyperkalemia) in the blood and severe dehydration. In particular, SCNN1A gene mutations are involved in autosomal recessive PHA1, a severe form of the condition that does not improve with age.

Most mutations in the SCNN1A gene result in a shortened alpha subunit protein of the ENaC channel. Other mutations delete a small piece of DNA or change a single protein building block (amino acid) in the alpha subunit protein. SCNN1A gene mutations lead to reduced or absent ENaC channel activity. As a result, sodium reabsorption is impaired, leading to hyponatremia and other signs and symptoms of autosomal recessive PHA1. The reduced function of ENaC channels in lung epithelial cells leads to excess fluid in the lungs and recurrent lung infections.

Other disorders

Some people with cystic fibrosis-like syndrome have a mutation or a normal gene variation (polymorphism) in the SCNN1A gene. People with cystic fibrosis-like syndrome (also known as atypical cystic fibrosis or bronchiectasis with or without elevated sweat chloride type 2) have signs and symptoms that resemble those of cystic fibrosis, including breathing problems and lung infections. However, changes in the gene most commonly associated with cystic fibrosis, CFTR, cannot explain development of the condition. It is thought that a mutation or gene variation in the SCNN1A gene can disrupt sodium transport and fluid balance, which leads to the signs and symptoms of cystic fibrosis-like syndrome.

Other Names for This Gene

• alpha-ENaC
• alpha-NaCH
• amiloride-sensitive epithelial sodium channel alpha subunit
• amiloride-sensitive sodium channel subunit alpha
• BESC2
• ENaCa
• ENaCalpha
• epithelial Na(+) channel subunit alpha
• FLJ21883
• nasal epithelial sodium channel alpha subunit
• nonvoltage-gated sodium channel 1 subunit alpha
• SCNEA
• SCNN1
• SCNNA_HUMAN
• sodium channel, non voltage gated 1 alpha subunit
• sodium channel, non-voltage-gated 1 alpha subunit
• sodium channel, nonvoltage-gated 1 alpha

Genomic Location

Normal Function

The SCNN1B gene provides instructions for making one piece, the beta subunit, of a protein complex called the epithelial sodium channel (ENaC). The channel is composed of alpha, beta, and gamma subunits, each of which is produced from a different gene. These channels are found at the surface of certain cells called epithelial cells in many tissues of the body, including the kidneys, lungs, colon, and sweat glands. The ENaC channel transports sodium into cells.

In the kidney, ENaC channels open in response to signals that sodium levels in the blood are too low, which allows sodium to flow into cells. From the kidney cells, this sodium is returned to the bloodstream (a process called reabsorption) rather than being removed from the body in urine. In addition to regulating the amount of sodium in the body, the flow of sodium ions helps control the movement of water in tissues. For example, ENaC channels in lung cells help regulate the amount of fluid in the lungs.

Health Conditions Related to Genetic Changes

Liddle syndrome

At least 16 mutations in the SCNN1B gene can cause a condition known as Liddle syndrome. People with Liddle syndrome have high blood pressure (hypertension) and low levels of potassium in their blood (hypokalemia), often beginning in childhood. Mutations in the SCNN1B gene associated with Liddle syndrome lead to the production of an abnormally short beta subunit protein or result in the replacement of a single protein building block (amino acid) in the protein. These changes affect an important region of the protein involved in signaling for its breakdown (degradation). As a result of the mutations, the protein is not degraded, and more ENaC channels remain at the cell surface. The increase in channels at the cell surface abnormally increases the reabsorption of sodium (followed by water), which leads to hypertension. Reabsorption of sodium into the blood is linked with removal of potassium from the blood, so excess sodium reabsorption leads to hypokalemia.

Pseudohypoaldosteronism type 1

Mutations in the SCNN1B gene have been identified in people with pseudohypoaldosteronism type 1 (PHA1). This condition typically begins in infancy and is characterized by low levels of sodium (hyponatremia) and high levels of potassium (hyperkalemia) in the blood, and severe dehydration due to the loss of excess sodium and fluid in urine. In particular, SCNN1B gene mutations are involved in autosomal recessive PHA1, a severe form of the condition that does not improve with age.

Mutations in the SCNN1B gene that cause PHA1 often result in the replacement of a single amino acid in the beta subunit protein or lead to an abnormally short protein. These mutations result in reduced or absent ENaC channel activity. As a result, sodium reabsorption is impaired, leading to hyponatremia and other signs and symptoms of autosomal recessive PHA1. The reduced function of ENaC channels in lung epithelial cells leads to excess fluid in the lungs and recurrent lung infections.

Other disorders

Some people with cystic fibrosis-like syndrome have a mutation or a normal gene variation (polymorphism) in the SCNN1B gene. People with cystic fibrosis-like syndrome (also known as atypical cystic fibrosis or bronchiectasis with or without elevated sweat chloride type 1) have signs and symptoms that resemble those of cystic fibrosis, including breathing problems and lung infections. However, changes in the gene most commonly associated with cystic fibrosis, CFTR, cannot explain development of the condition. It is thought that a mutation or gene variation in the SCNN1B gene can disrupt sodium transport and fluid balance, which leads to the signs and symptoms of cystic fibrosis-like syndrome.

Other Names for This Gene

• amiloride-sensitive sodium channel subunit beta
• BESC1
• beta-ENaC
• beta-NaCH
• ENaCb
• ENaCbeta
• epithelial Na(+) channel subunit beta
• nasal epithelial sodium channel beta subunit
• SCNEB
• SCNNB_HUMAN
• sodium channel, non voltage gated 1 beta subunit
• sodium channel, non-voltage-gated 1, beta subunit
• sodium channel, nonvoltage-gated 1, beta

Genomic Location

Normal Function

The SCNN1G gene provides instructions for making one piece, the gamma subunit, of a protein complex called the epithelial sodium channel (ENaC). The channel is composed of alpha, beta, and gamma subunits, each of which is produced from a different gene. These channels are found at the surface of certain cells called epithelial cells in many tissues of the body, including the kidneys, lungs, and sweat glands. The ENaC channel transports sodium into cells.

In the kidney, ENaC channels open in response to signals that sodium levels in the blood are too low, which allows sodium to flow into cells. From the kidney cells, this sodium is returned to the bloodstream (a process called reabsorption) rather than being removed from the body in urine. In addition to regulating the amount of sodium in the body, the flow of sodium ions helps control the movement of water in tissues. For example, ENaC channels in lung cells help regulate the amount of fluid in the lungs.

Health Conditions Related to Genetic Changes

Liddle syndrome

At least 5 mutations in the SCNN1G gene can cause a condition known as Liddle syndrome. People with Liddle syndrome have high blood pressure (hypertension) and low levels of potassium in their blood (hypokalemia), often beginning in childhood. Mutations in the SCNN1G gene associated with Liddle syndrome lead to the production of an abnormally short gamma subunit protein. These changes affect an important region of the gamma subunit protein involved in signaling for its breakdown (degradation). As a result of the mutations, the protein is not degraded, and more ENaC channels remain at the cell surface. The increase in channels at the cell surface allows the reabsorption of excess sodium (followed by water), which leads to hypertension. Reabsorption of sodium into the blood is linked with removal of potassium from the blood, so excess sodium reabsorption leads to hypokalemia.

Pseudohypoaldosteronism type 1

Mutations in the SCNN1G gene are involved in a condition called pseudohypoaldosteronism type 1 (PHA1). This condition typically begins in infancy and is characterized by low levels of sodium (hyponatremia) and high levels of potassium (hyperkalemia) in the blood, and severe dehydration due to the loss of excess sodium and fluid in urine. In particular, SCNN1G gene mutations are involved in autosomal recessive PHA1, a severe form of the condition that does not improve with age.

Most mutations in the SCNN1G gene lead to an abnormally short gamma subunit protein. These mutations result in reduced or absent ENaC channel activity. As a result, sodium reabsorption is impaired, leading to hyponatremia and other signs and symptoms of autosomal recessive PHA1. The reduced function of ENaC channels in lung epithelial cells leads to excess fluid in the lungs and recurrent lung infections.

Other disorders

Some people with cystic fibrosis-like syndrome have a mutation or a normal gene variation (polymorphism) in the SCNN1G gene. People with cystic fibrosis-like syndrome (also known as atypical cystic fibrosis or bronchiectasis with or without elevated sweat chloride type 3) have signs and symptoms that resemble those of cystic fibrosis, including breathing problems and lung infections. However, changes in the gene most commonly associated with cystic fibrosis, CFTR, cannot explain development of the condition. It is thought that a mutation or gene variation in the SCNN1G gene can disrupt sodium transport and fluid balance, which leads to the signs and symptoms of cystic fibrosis-like syndrome.

Other Names for This Gene

• amiloride-sensitive epithelial sodium channel gamma subunit
• amiloride-sensitive sodium channel gamma-subunit
• amiloride-sensitive sodium channel subunit gamma
• BESC3
• ENaC gamma subunit
• ENaCg
• ENaCgamma
• epithelial Na(+) channel subunit gamma
• gamma-ENaC
• gamma-NaCH
• nonvoltage-gated sodium channel 1 subunit gamma
• SCNEG
• SCNNG_HUMAN
• sodium channel, non voltage gated 1 gamma subunit
• sodium channel, non-voltage-gated 1, gamma subunit
• sodium channel, nonvoltage-gated 1, gamma

Genomic Location

PHA1 can have different inheritance patterns. When the condition is caused by mutations in the NR3C2 gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. When PHA1 is caused by mutations in the SCNN1A, SCNN1B, or SCNN1G genes, it is 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.

PHA1 is a rare condition that has been estimated to affect 1 in 80,000 newborns.