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

Nadia Mastroianni, Alberto Bettinelli, Mario Bianchetti, Giacomo Colussi, Maurizio De Fusco, Fabio Sereni, Andrea Ballabio, Giorgio Casari

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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.

Original languageEnglish
Pages (from-to)1019-1026
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 1996

ASJC Scopus subject areas

  • Genetics


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