title: Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes.
abstract: OBJECTIVE
  Gitelman's syndrome (GS) is an inherited autosomal recessive disorder due to loss of function mutations in the SLC12A3 gene encoding the Na-Cl co-transporter (NCCT), the target of thiazide diuretics. The defective function of the NCCT, which normally is expressed in the apical membrane of the distal convolute tubule in the kidney, leads to mild hypotension, hypokalemia, hyperreninemic hyperaldosteronism, mild metabolic alkalosis, hypomagnesemia and hypocalciuria. Up to now, more than 100 mutations of the SLC12A3 gene have been described in GS patients.
  
  
  METHODS
  We have collected 30 patients from Sweden with a clinical diagnosis of GS and undertaken a mutation screening by SSCP and successive sequencing of the 26 exons and intronic boundaries. Both mutations were identified in most (n = 28, 93%) and at least one mutation was identified in all patients.
  
  
  RESULTS
  We found 22 different mutations evenly distributed throughout the gene, 11 of which have not been described previously. The new variants include 8 missense mutations (Glu68Lys, His69Asn, Argl45His, Vall53Met, Gly230Asp, Gly342Ala, Val677Leu and Gly867Ser), 1 insertion (c.834_835insG on exon 6) and 2 splice-site mutations (c.2667 + lT>G substitution in splicing donor site after exon 22, c.1569-1G>A substitution in the splicing acceptor site before exon 13).
  
  
  CONCLUSIONS
  In Swedish patients with the clinical features of GS, disease-causing mutations in the SLC12A3 gene were identified in most patients. The spectrum of GS mutations is wide making full mutation screening of the SLC12A3 gene necessary to confirm the diagnosis.
authors.affiliation: Division of Endocrinology, Department of Clinical Sciences, University of Malmö, Malmo, Sweden. christiano.fava@med.lu.se
authors.forename: Cristiano
authors.initials: C
authors.lastname: Fava
authors.forename: Martina
authors.initials: M
authors.lastname: Montagnana
authors.forename: Lena
authors.initials: L
authors.lastname: Rosberg
authors.forename: Philippe
authors.initials: P
authors.lastname: Burri
authors.forename: Anders
authors.initials: A
authors.lastname: Jönsson
authors.forename: Pär
authors.initials: P
authors.lastname: Wanby
authors.forename: Hans
authors.initials: H
authors.lastname: Wahrenberg
authors.forename: U Lennart
authors.initials: UL
authors.lastname: Hulthén
authors.forename: Mattias
authors.initials: M
authors.lastname: Aurell
authors.forename: Gian Cesare
authors.initials: GC
authors.lastname: Guidi
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
mesh_terms: D017668:Age of Onset; D005091:Exons; D005808:Genes, Recessive; D005820:Genetic Testing; D014644:Genetic Variation; D053579:Gitelman Syndrome / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007438:Introns; D008957:Models, Genetic; D016254:Mutagenesis, Insertional; D009154:Mutation; D020125:Mutation, Missense; D018807:Polymorphism, Single-Stranded Conformational; D022821:RNA Splice Sites / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics*; D064486:Solute Carrier Family 12, Member 3; D013548:Sweden; D027981:Symporters / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; D011955:Receptors, Drug; C578874:SLC12A3 protein, human; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters