Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter

• Published in: Nature genetics Vol. 12; no. 1; pp. 24 - 30
• Main Authors: SIMON, D. B, NELSON-WILLIAMS, C, GAINZA, F. J, GITELMAN, H. J, LIFTON, R. P, BIA, M. J, ELLISON, D, KARET, F. E, MOLINA, A. M, VAARA, I, IWATA, F, CUSHNER, H. M, KOOLEN, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 1996
• Subjects: Amino Acid Sequence; Animals; Bartter Syndrome - genetics; Base Sequence; Biological and medical sciences; Biological Transport; Carrier Proteins - genetics; Chlorides - metabolism; Chromosomes, Human, Pair 16; Cloning, Molecular; Dinucleotide Repeats; DNA Primers - chemistry; Female; Flounder; Genetic Linkage; Glomerulonephritis; Humans; Male; Medical sciences; Molecular Sequence Data; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Pedigree; Point Mutation; Polymorphism, Single-Stranded Conformational; Rats; Receptors, Drug - genetics; Sequence Alignment; Sodium - metabolism; Sodium Chloride Symporters; Solute Carrier Family 12, Member 3; Symporters; Endocrinopathy; Hydroelectrolytic balance disorder; Membrane protein; Adrenal cortex diseases; Hyperaldosteronism; Metabolic alkalosis; Biological transport; Renal disease; Homology; Hyperadrenocorticism; Inorganic element; Gene; Chlorides; Adrenal gland diseases; Genetics; Genetic mapping; Human; Urinary system disease; Linkage; Nucleotide sequence; Genetic disease; Bartter syndrome; Metabolic disorder; Chromosome E16; Sodium; Chromosome DNA; Hypokaliemia; Mutation; Potassium
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng0196-24

Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function. Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelman's syndrome to the locus encoding the renal thiazide-sensitive Na-Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects. These findings demonstrate the molecular basis of Gitelman's syndrome. We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.