Scientific background:

Summary: The gene encodes the thiazide-sensitive sodium-chloride co-trasnporter. Mutations cause Gitelman syndrome.

Gene: The gene is about 49 kb in size. It was recovered as the receptor for thiazide diuretics (NCCT, TSC). The current acronym is SLC12A3 because it belongs to solute cotransporters. It is located on chromosome 16 at position 16q13. The gene consists of 26 exons.

Pathology: The translation product is a protein of 112 kD (1,021 amino acids). This protein consists of 12 membrane spanning domains and 2 intracellular hydrophilic amino and carboxyl termini. The gene is predominantly expressed in kidneys, in the distal convoluted tubule. Its main task is sodium reabsorbtion. Thiazides block this cotransporter.

Clinical signs: The clinical picture of loss-of-function mutations in this gene is known as Gitelman syndrome. It is an autosomal recessive disorder disorder characterized by metabolic alkalosis, hypokalemia, hypomagnesemia, and hypocalciuria. Clinical symptoms are similar to overdosage of thiazides. ECG changes consistend with long QT syndrome also have been reported.

Epidemiology: Only few families are known so far. About 50 mutations are identified.

Test strategy: Predominant indications for molecular diagnostic are family counseling and improvement of diagnostic precision.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		medium
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Multiplex Ligation-Dependent Probe Amplification
		Turn-around time		25 working days
		Effort		medium
		Specimen		DNA
		Quality assessment		Internal quality control only
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.

Literature: 

Cruz DN et al. (2001) Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life.
Bettinelli A et al. (1995) Genetic heterogeneity in tubular hypomagnesemia-hypokalemia with hypocalcuria (Gitelman's syndrome).
Simon DB et al. (1996) Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.
Roser M et al. (2009) Gitelman syndrome.