Spectrum of mutations in Gitelman syndrome.

نویسندگان

  • Rosa Vargas-Poussou
  • Karin Dahan
  • Diana Kahila
  • Annabelle Venisse
  • Eva Riveira-Munoz
  • Huguette Debaix
  • Bernard Grisart
  • Franck Bridoux
  • Robert Unwin
  • Bruno Moulin
  • Jean-Philippe Haymann
  • Marie-Christine Vantyghem
  • Claire Rigothier
  • Bertrand Dussol
  • Michel Godin
  • Hubert Nivet
  • Laurence Dubourg
  • Ivan Tack
  • Anne-Paule Gimenez-Roqueplo
  • Pascal Houillier
  • Anne Blanchard
  • Olivier Devuyst
  • Xavier Jeunemaitre
چکیده

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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عنوان ژورنال:
  • Journal of the American Society of Nephrology : JASN

دوره 22 4  شماره 

صفحات  -

تاریخ انتشار 2011