Gitelman syndrome is a kidney disorder that causes an imbalance of charged atoms (ions) in the body, including ions of potassium, magnesium, and calcium.

The signs and symptoms of Gitelman syndrome usually appear in late childhood or adolescence. Common features of this condition include painful muscle spasms (tetany), muscle weakness or cramping, dizziness, and salt craving. Also common is a tingling or prickly sensation in the skin (paresthesias), most often affecting the face. Some individuals with Gitelman syndrome experience excessive tiredness (fatigue), low blood pressure, and a painful joint condition called chondrocalcinosis. Studies suggest that Gitelman syndrome may also increase the risk of a potentially dangerous abnormal heart rhythm called ventricular arrhythmia.

The signs and symptoms of Gitelman syndrome vary widely, even among affected members of the same family. Most people with this condition have relatively mild symptoms, although affected individuals with severe muscle cramping, paralysis, and slow growth have been reported.

Gitelman syndrome is usually caused by mutations in the SLC12A3 gene. Less often, the condition results from mutations in the CLCNKB gene. The proteins produced from these genes are involved in the kidneys' reabsorption of salt (sodium chloride or NaCl) from urine back into the bloodstream. Mutations in either gene impair the kidneys' ability to reabsorb salt, leading to the loss of excess salt in the urine (salt wasting). Abnormalities of salt transport also affect the reabsorption of other ions, including ions of potassium, magnesium, and calcium. The resulting imbalance of ions in the body underlies the major features of Gitelman syndrome.

Normal Function

The SLC12A3 gene provides instructions for making a protein known as NCC. This protein is a sodium chloride co-transporter, which means that it moves charged atoms (ions) of sodium (Na+) and chlorine (Cl-) across cell membranes.

The NCC protein is essential for normal kidney function. It is part of the mechanism by which kidneys reabsorb salt (sodium chloride or NaCl) from the urine back into the bloodstream. The retention of salt affects the body's fluid levels and helps maintain blood pressure.

Health Conditions Related to Genetic Changes

Gitelman syndrome

More than 140 mutations in the SLC12A3 gene have been identified in people with Gitelman syndrome. Most of these mutations change single protein building blocks (amino acids) in the NCC co-transporter protein. These mutations prevent the protein from reaching the cell membrane or alter the protein's ability to transport sodium and chloride ions. Other mutations in the SLC12A3 gene insert or delete genetic material or lead to the production of an abnormally short, nonfunctional version of the NCC protein.

Mutations in the SLC12A3 gene impair the kidneys' ability to reabsorb salt, leading to the loss of excess salt in the urine (salt wasting). Abnormalities of salt transport also affect the reabsorption of other ions, including ions of potassium, magnesium, and calcium. The resulting imbalance of ions in the body underlies the major features of Gitelman syndrome.

Other disorders

Some research suggests that normal variants (polymorphisms) in the SLC12A3 gene may help explain differences in blood pressure between people. Certain rare polymorphisms also appear to protect against high blood pressure (hypertension). Changes in the SLC12A3 gene may affect blood pressure by altering the kidneys' ability to reabsorb salt into the bloodstream. However, some studies have not found any association between variants in the SLC12A3 gene and blood pressure.

Other Names for This Gene

• Na-Cl symporter
• NaCl electroneutral thiazide-sensitive cotransporter
• NCCT
• S12A3_HUMAN
• solute carrier family 12 (sodium/chloride transporter), member 3
• solute carrier family 12 (sodium/chloride transporters), member 3
• thiazide-sensitive Na-Cl cotransporter
• thiazide-sensitive sodium-chloride cotransporter
• TSC

Genomic Location

Normal Function

The CLCNKB gene belongs to the CLC family of genes, which provide instructions for making chloride channels. These channels, which transport negatively charged chlorine atoms (chloride ions), play a key role in a cell's ability to generate and transmit electrical signals. Some CLC channels regulate the flow of chloride ions across cell membranes, while others transport chloride ions within cells.

The CLCNKB gene provides instructions for making a chloride channel called ClC-Kb. These channels are found predominantly in the kidneys. ClC-Kb is one of several proteins that work together to regulate the movement of ions into and out of kidney cells. The transport of chloride ions by ClC-Kb channels is part of the mechanism by which the kidneys reabsorb salt (sodium chloride or NaCl) from the urine back into the bloodstream. The retention of salt affects the body's fluid levels and helps maintain blood pressure.

ClC-Kb channels are also located in the inner ear, where they play a role in normal hearing.

Health Conditions Related to Genetic Changes

Bartter syndrome

More than 30 mutations in the CLCNKB gene have been identified in people with Bartter syndrome type III. This form of the condition, which is also described as classical Bartter syndrome, begins in childhood and tends to be less severe than other types of Bartter syndrome.

Many of the mutations responsible for Bartter syndrome type III delete the entire CLCNKB gene. Other mutations change single protein building blocks (amino acids) in the ClC-Kb channel or lead to an abnormally short, nonfunctional version of ClC-Kb. A loss of functional ClC-Kb channels impairs the transport of chloride ions in the kidneys. As a result, the kidneys cannot reabsorb salt normally and excess salt is lost through the urine (salt wasting). The abnormal salt loss disrupts the normal balance of ions in the body. This imbalance underlies many of the major features of Bartter syndrome type III.

Several people with a more severe form of Bartter syndrome have had mutations in both the CLCNKB gene and a closely related gene called CLCNKA. The CLCNKA gene provides instructions for making a very similar chloride channel, ClC-Ka, that is also found in the kidneys and inner ear. A combination of CLCNKA and CLCNKB gene mutations causes a life-threatening form of the disorder known as Bartter syndrome type IV or antenatal Bartter syndrome with sensorineural deafness. In addition to salt wasting, this form of the disorder is characterized by hearing loss that results from a loss of ClC-Ka and ClC-Kb function in the inner ear.

Gitelman syndrome

Mutations in the CLCNKB gene are a rare cause of Gitelman syndrome. Like the mutations responsible for Bartter syndrome, the genetic changes associated with Gitelman syndrome impair the kidneys' ability to reabsorb salt, leading to salt wasting. Abnormalities of salt transport also affect the reabsorption of other ions, including ions of potassium, magnesium, and calcium. The resulting imbalance of ions in the body leads to the characteristic features of Gitelman syndrome.

Other disorders

A common variation (polymorphism) in the CLCNKB gene has been associated with salt-sensitive hypertension, a form of high blood pressure related to increased levels of salt in the blood. The polymorphism replaces the amino acid threonine with the amino acid serine at position 481 in the ClC-Kb channel (also written as Thr481Ser or T481S). This genetic change increases the activity of the ClC-Kb channel, which directs the kidneys to reabsorb more salt into the bloodstream. The excess salt raises blood pressure and increases the risk of developing hypertension.

Other Names for This Gene

• chloride channel Kb
• chloride channel protein ClC-Kb
• chloride channel, kidney, B
• chloride channel, voltage-sensitive Kb
• ClC-K2
• ClC-Kb
• CLCKB
• CLCKB_HUMAN
• hClC-Kb

Genomic Location

• 25% (1 in 4) chance to be affected
• 50% (1 in 2) chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not be a carrier