Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.
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.
Simon
D B
DB
Howard Hughes Medical Institute, Department of Genetics, Boyer Center for Molecular Medicine, New Haven, Connecticut, USA.
Nelson-Williams
C
C
Bia
M J
MJ
Ellison
D
D
Karet
F E
FE
Molina
A M
AM
Vaara
I
I
Iwata
F
F
Cushner
H M
HM
Koolen
M
M
Gainza
F J
FJ
Gitleman
H J
HJ
Lifton
R P
RP
D000595:Amino Acid Sequence; D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics*; D001483:Base Sequence; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics*; D002712:Chlorides / Q000378:metabolism*; D002885:Chromosomes, Human, Pair 16; D003001:Cloning, Molecular; D017931:DNA Primers / Q000737:chemistry; D018900:Dinucleotide Repeats; D005260:Female; D005432:Flounder; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D051381:Rats; D011955:Receptors, Drug / Q000235:genetics*; D016415:Sequence Alignment; D012964:Sodium / Q000378:metabolism*; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters
D002352:Carrier Proteins; D002712:Chlorides; D017931:DNA Primers; D011955:Receptors, Drug; C578874:SLC12A3 protein, human; C578876:Slc12a3 protein, rat; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; C064415:thiazide receptor; D012964:Sodium