Novel molecular variants of the Na-Cl cotransporter gene are responsible for Gitelman syndrome

Am J Hum Genet. 1996 Nov;59(5):1019-26.


A hereditary defect of the distal tubule accounts for the clinical features of Gitelman syndrome (GS), an autosomal recessive disease characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. Recently, we cloned the cDNA coding for the human Na-Cl thiazide-sensitive cotransporter (TSC; also known as ¿NCCT¿ or ¿SLC12A3¿) as a possible candidate for GS, and Simon et al., independently, described mutations in patients with GS. Now, we show 12 additional mutations consistent with a loss of function of the Na-Cl cotransporter in GS. Two missense replacements, R209W and P349L, are common to both studies and could represent ancient mutations. The other mutations include three deletions, two insertions, and six missense mutations. When all mutations from both studies are considered, missense mutations seem to be more frequently localized within the intracellular domains of the molecule, rather than in transmembrane or extracellular domains. One family, previously reported as a GS form with dominant inheritance, has proved to be recessive, with the affected child being a compound heterozygote. A highly informative intragenic tetranucleotide marker, useful for molecular diagnostic studies, has been identified at the acceptor splice site of exon 9.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alkalosis / genetics*
  • Alkalosis / metabolism
  • Biomarkers
  • Calcium / urine
  • Carrier Proteins / genetics*
  • DNA Primers
  • Exons / genetics
  • Female
  • Humans
  • Hypokalemia / genetics*
  • Hypokalemia / metabolism
  • Magnesium / urine
  • Magnesium Deficiency / genetics*
  • Magnesium Deficiency / metabolism
  • Male
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Sodium-Potassium-Chloride Symporters
  • Syndrome


  • Biomarkers
  • Carrier Proteins
  • DNA Primers
  • Sodium-Potassium-Chloride Symporters
  • Magnesium
  • Calcium

Associated data

  • GENBANK/X91220