Gitelman syndrome ... (Gitelman syndrome) - Genes SLC12A3 and CLCNKB.
Gitelman syndrome is a renal disorder that leads to an ion imbalance in the body, including potassium, magnesium and calcium ions. Signs and symptoms of Gitelman syndrome usually appear in late childhood or adolescence. The common features include tetany, muscle weakness or cramps, dizziness, tingling or numbness that most often affects the face, fatigue, low blood pressure and chondrocalcinosis. Studies suggest that Gitelman syndrome may also increase the risk of ventricular arrhythmia. These signs and symptoms vary widely, even among affected members of the same family. Most people with this disease have relatively mild symptoms, although there have been people affected with severe muscle cramps, paralysis and slow growth.
Most cases of Gitelman syndrome are caused by mutations in the SLC12A3 gene. Less often, this disease is due to mutations in the gene CLCNKB. The proteins encoded from these genes are involved in the reabsorption of the kidneys of sodium chloride or NaCl urine into the bloodstream.
The SLC12A3 gene, located on the long arm of chromosome 16 (16q13), encodes a protein known as NCC. This protein is a sodium chloride-co conveyor, which means that transports sodium and chloride ions across cell membranes. The NCC protein is essential for normal kidney function. It is part of the mechanism by which sodium chloride kidneys reabsorbed from the urine back into the blood stream. Salt retention affects the levels of body fluids and helps maintain blood pressure. There are more than 140 mutations in the SLC12A3 gene in people with Gitelman syndrome. Most of these mutations change the amino acid co-transporter protein NCC. These mutations prevent protein to reach the cell membrane or alter the ability of the protein to transport sodium and chloride ions. Other mutations in the SLC12A3 gene inserted or deleted genetic material encoding or lead to an abnormally short, nonfunctional version of the NCC protein. All mutations affect the ability of the kidneys to reabsorb salt, leading to loss of salt. Abnormalities in salt transport also affect reuptake other ions, including potassium, magnesium and calcium ions. The resulting imbalance of ions in the body underlying the main features of Gitelman syndrome.
The CLCNKB gene, located on the short arm of chromosome 1 (1p36), belongs to the family of CLC genes encoding chloride channels. These channels, which transport of chloride ions play a key role in the ability of a cell to generate and transmit electrical signals. Some CLC channels regulate the flow of chloride ions across cell membranes, while others transport of chloride ions inside cells. Specifically, the gene encodes CLCNKB the chloride channel ClC-Kb. These channels are found predominantly in the kidneys. ClC-Kb, is one of several proteins that act together to regulate the movement of ions inside and outside of the renal cells. The transport of chloride ion channels ClC-Kb is part of the mechanism by which the kidney reabsorb sodium chloride or NaCl from the urine back into the blood stream. Salt retention affects the levels of body fluids and help maintain blood pressure. The CLC-Kb channels are also found in the inner ear, where they play a role in normal hearing. Mutations in the gene CLCNKB are a rare cause of Gitelman syndrome. Like other mutations responsible for this syndrome, genetic changes associated with Gitelman syndrome affect the ability of the kidneys to reabsorb salt, leading to loss of salt. Abnormalities in salt transport also affect reuptake other ions, including potassium, magnesium and calcium ions. The resulting imbalance of ions in the body leads to the characteristic features of Gitelman syndrome.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Gitelman syndrome, by complete PCR amplification of the exons of SLC12A3 and CLCNKB genes, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).