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Spectrum of mutations in Gitelman syndrome.

Abstract : Gitelman's syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCC). Because 18 to 40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements may account for unidentified mutations. Here, we directly sequenced genomic DNA from a large cohort of 448 unrelated patients suspected of having GS. We found 172 distinct mutations, of which 100 were unreported previously. In 315 patients (70%), we identified two mutations; in 81 patients (18%), we identified one; and in 52 patients (12%), we did not detect a mutation. In 88 patients, we performed a search for large rearrangements by multiplex ligation-dependent probe amplification (MLPA) and found nine deletions and two duplications in 24 of the 51 heterozygous patients. A second technique confirmed each rearrangement. Based on the breakpoints of seven deletions, nonallelic homologous recombination by Alu sequences and nonhomologous end-joining probably favor these intragenic deletions. In summary, missense mutations account for approximately 59% of the mutations in Gitelman's syndrome, and there is a predisposition to large rearrangements (6% of our cases) caused by the presence of repeated sequences within the SLC12A3 gene.
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Contributor : Claire Carrion <>
Submitted on : Wednesday, February 12, 2014 - 5:03:21 PM
Last modification on : Wednesday, May 26, 2021 - 8:08:02 PM

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Rosa Vargas-Poussou, Karin Dahan, Diana Kahila, Annabelle Venisse, Eva Riveira-Munoz, et al.. Spectrum of mutations in Gitelman syndrome.. Journal of the American Society of Nephrology, American Society of Nephrology, 2011, 22 (4), pp.693-703. ⟨10.1681/ASN.2010090907⟩. ⟨hal-00945691⟩



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