title: Evaluating PVALB as a candidate gene for SLC12A3-negative cases of Gitelman's syndrome.
abstract: BACKGROUND
  Loss-of-function mutations in SLC12A3 coding for the thiazide-sensitive NaCl cotransporter (NCC) cause Gitelman's syndrome (GS), a recessively inherited salt-losing tubulopathy. Most GS patients are compound heterozygous. However, up to 30% of GS patients carry only a single mutant allele, and a normal SLC12A3 screening is also observed in a small subset of patients. Locus heterogeneity could explain the lack of detection of mutant SLC12A3 alleles in GS patients. The renal phenotype of the parvalbumin knockout mice pointed to PVALB as a candidate gene for GS for SLC12A3-negative cases.
  
  
  METHODS
  PCR and direct sequencing of PVALB was performed in 132 GS patients in whom only one or no (N = 79) mutant SLC12A3 allele was found. The possible interference of biallelic SNPs (single nucleotide polymorphisms) on normal transcription or normal splicing was investigated. Genotyping of 110 anonymous blood donors was performed to determine the allelic frequency in the normal population.
  
  
  RESULTS
  No sequence variants resulting in amino acid substitution or truncated protein within the PVALB gene were found in the 264 chromosomes tested. Ten biallelic SNPs, including six novel polymorphisms, were identified: five in the 5' UTR, none of them affecting predicted regulatory elements; three in the coding region, without alteration of the consensus splice sites, and two in the 3' UTR. The observed allelic frequencies did not differ significantly between GS patients and controls.
  
  
  CONCLUSIONS
  Our results strongly suggest that mutations in the PVALB gene are not involved in GS patients who harbour a single or no mutant SLC12A3 allele.
authors.affiliation: Division of Nephrology, Université catholique de Louvain, 10 Avenue Hippocrate, Brussels B-1200, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Riveira-Munoz
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Hendrica
authors.initials: H
authors.lastname: Belge
authors.forename: Nikola
authors.initials: N
authors.lastname: Jeck
authors.forename: Laurence
authors.initials: L
authors.lastname: Strompf
authors.forename: Rosa
authors.initials: R
authors.lastname: Vargas-Poussou
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaître
authors.forename: Anne
authors.initials: A
authors.lastname: Blanchard
authors.forename: Nine V
authors.initials: NV
authors.lastname: Knoers
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
authors.forename: Karin
authors.initials: K
authors.lastname: Dahan
mesh_terms: D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D053579:Gitelman Syndrome / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010320:Parvalbumins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011955:Receptors, Drug / Q000235:genetics*; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000235:genetics*
chemical_list: D017931:DNA Primers; D010320:Parvalbumins; D011955:Receptors, Drug; C578874:SLC12A3 protein, human; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters