Hereditary sensory and autonomic neuropathy type II (HSAN2) is a condition that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, temperature, and touch to the brain. These sensations are impaired in people with HSAN2. In some affected people, the condition may also cause mild abnormalities of the autonomic neurons, which control involuntary body functions such as heart rate, digestion, and breathing. The sensory and autonomic neurons are part of the body's peripheral nervous system, which comprises the nerves outside the brain and spinal cord. HSAN2 is considered a form of peripheral neuropathy.

The signs and symptoms of HSAN2 typically begin in infancy or early childhood. The first sign of the condition is usually numbness in the hands and feet. Soon after, affected individuals lose the ability to feel pain or sense hot and cold. In people with HSAN2, unnoticed injuries often lead to open sores (ulcers) on the hands and feet. Because affected individuals cannot feel the pain of these sores, they may not seek treatment right away. Without treatment, the ulcers can become infected and may require amputation of the affected area. People with HSAN2 often injure themselves unintentionally, typically by biting the tongue, lips, or fingers. These injuries may lead to loss of the affected areas, such as the tip of the tongue. Affected individuals often have injuries and fractures in their hands, feet, limbs, and joints that go untreated because of the inability to feel pain. Repeated injury can lead to a condition called Charcot joints, in which the bones and tissue surrounding joints are damaged.

The effects of HSAN2 on the autonomic nervous system are more variable. Some infants with HSAN2 have digestive problems such as the backflow of stomach acids into the esophagus (gastroesophageal reflux) or slow eye-blink or gag reflexes. Affected individuals may also have weak deep-tendon reflexes, such as the reflex being tested when a doctor taps the knee with a hammer.

Some people with HSAN2 lose a type of taste bud on the tip of the tongue called lingual fungiform papillae and have a diminished sense of taste.

There are several types of HSAN2, each caused by mutations in a different gene. HSAN2A is caused by mutations in the WNK1 gene, and HSAN2B is caused by mutations in the RETREG1 gene. Additional types caused by mutations in other genes are rare. Although different genes are involved, all types of HSAN2 have similar signs and symptoms.

The WNK1 gene provides instructions for making multiple versions (isoforms) of the WNK1 protein. HSAN2A is caused by mutations that affect a particular isoform called the WNK1/HSN2 protein. This protein is found in the cells of the nervous system, including sensory neurons. The mutations involved in HSAN2A result in an abnormally short WNK1/HSN2 protein. Although the function of this protein is not well understood, it is likely that the abnormally short version cannot function properly or is broken down. People with HSAN2A have a reduction in the number of sensory neurons; however, the role that WNK1/HSN2 protein changes play in that loss is unclear.

HSAN2B is caused by mutations in the RETREG1 gene. These mutations lead to an abnormally short and nonfunctional protein. The RETREG1 protein is normally found in sensory and autonomic neurons. It is involved in the recycling of worn-out cell parts (autophagy), specifically a cell structure called the endoplasmic reticulum. When the RETREG1 protein is nonfunctional, recycling of the endoplasmic reticulum is impaired. The buildup of these structures likely results in death of the neurons.

The loss of neurons leads to the inability to feel pain, temperature, and touch sensations and to the impairment of the autonomic nervous system seen in people with HSAN2.

Normal Function

The RETREG1 gene provides instructions for making a protein that is involved in a cellular process called autophagy. Cells use this process to recycle worn-out or unnecessary cell parts and break down certain proteins when they are no longer needed. In particular, the RETREG1 protein helps direct autophagy of a cell structure called the endoplasmic reticulum, which is important in protein processing and transport. Autophagy may be a way for the cell to remove parts of the endoplasmic reticulum when they are no longer needed or to break down excess or abnormal proteins that are being processed within the structure.

The RETREG1 protein also appears to be important in the organization of another cell structure called the Golgi apparatus, which is important for distribution of proteins within the cell.

The RETREG1 protein is found in sensory and autonomic nerve cells (neurons). Sensory neurons transmit pain, touch, and temperature sensations. Autonomic neurons help control involuntary functions of the body such as heart rate and blood pressure.

Health Conditions Related to Genetic Changes

Hereditary sensory and autonomic neuropathy type II

Mutations in the RETREG1 gene are responsible for one type of hereditary sensory and autonomic neuropathy type II (HSAN2) called HSAN2B; at least five mutations have been identified in affected individuals. People with HSAN2B lose the ability to feel pain or sense hot and cold. The RETREG1 gene mutations may lead to an abnormally short and nonfunctional protein. The resulting lack of functioning RETREG1 protein impairs autophagy of the endoplasmic reticulum and alters the structure of the Golgi apparatus in sensory and autonomic neurons.

Researchers suspect that an inability to break down parts of the endoplasmic reticulum when they are no longer needed, and the subsequent accumulation of these structures and other proteins in cells, leads to cell death. The loss of sensory and autonomic neurons due to impaired autophagy results in the signs and symptoms of HSAN2B. It is unclear what role abnormalities of the Golgi apparatus play in the condition.

Other Names for This Gene

• F134B_HUMAN
• FAM134B
• FAM134B protein
• FAM134B protein isoform 1
• FAM134B protein isoform 2
• family with sequence similarity 134 member B
• family with sequence similarity 134, member B
• FLJ20152
• FLJ22155
• FLJ22179
• JK1

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

This condition 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.

HSAN2 is a rare disease; however, the prevalence is unknown.