title: 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.
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France. rosa.vargas@egp.aphp.fr
authors.forename: Rosa
authors.initials: R
authors.lastname: Vargas-Poussou
authors.forename: Karin
authors.initials: K
authors.lastname: Dahan
authors.forename: Diana
authors.initials: D
authors.lastname: Kahila
authors.forename: Annabelle
authors.initials: A
authors.lastname: Venisse
authors.forename: Eva
authors.initials: E
authors.lastname: Riveira-Munoz
authors.forename: Huguette
authors.initials: H
authors.lastname: Debaix
authors.forename: Bernard
authors.initials: B
authors.lastname: Grisart
authors.forename: Franck
authors.initials: F
authors.lastname: Bridoux
authors.forename: Robert
authors.initials: R
authors.lastname: Unwin
authors.forename: Bruno
authors.initials: B
authors.lastname: Moulin
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Haymann
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
authors.forename: Claire
authors.initials: C
authors.lastname: Rigothier
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dussol
authors.forename: Michel
authors.initials: M
authors.lastname: Godin
authors.forename: Hubert
authors.initials: H
authors.lastname: Nivet
authors.forename: Laurence
authors.initials: L
authors.lastname: Dubourg
authors.forename: Ivan
authors.initials: I
authors.lastname: Tack
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.forename: Anne
authors.initials: A
authors.lastname: Blanchard
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D053579:Gitelman Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000235:genetics*; D055815:Young Adult
chemical_list: C412733:CLCNKB protein, human; D018118:Chloride Channels; D011955:Receptors, Drug; C578874:SLC12A3 protein, human; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters