Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Thiazide-sensitive NA-CL Cotransporter

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

Epidemiology

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

Gene Structure

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.

Phenotype

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.

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.

Test Strategy

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

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Multiplex Ligation-Dependent Probe Amplification
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA

Related Diseases:

Gitelman syndrome
SLC12A3

References:

1.

Cruz DN et al. (2001) Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life.

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2.

Roser M et al. (2009) Gitelman syndrome.

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3.

Bettinelli A et al. (1995) Genetic heterogeneity in tubular hypomagnesemia-hypokalemia with hypocalcuria (Gitelman's syndrome).

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4.

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.

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Update: Sept. 26, 2018