title: Analysis of renal tubular electrolyte transporter genes in seven patients with hypokalemic metabolic alkalosis.
abstract: BACKGROUND
  Disorders that manifest hypokalemic metabolic alkalosis, such as Bartter's syndrome and Gitelman's syndrome, are caused by the malfunction of renal tubular electrolyte transporters. Bartter's syndrome may be linked to dysfunction of Na-K-2Cl cotransporter (NKCC2), renal outer medullary K channel (ROMK), or Cl channel Kb (ClC-Kb), while Gitelman's syndrome may be linked to Na-Cl cotransporter (NCCT) dysfunction. However, previous genetic analyses in these syndromes have included many heterozygotes for each gene and there has been no further analysis of other genes. Thus, to clarify the interaction of these transporter genes, in the present study we investigated all 4 transporter genes in 7 patients with hypokalemic metabolic alkalosis.
  
  
  METHODS
  Seven patients from 5 families (patients A-G) were collected, and a mutation analysis of the 4 renal electrolyte transporter genes was performed by direct sequencing.
  
  
  RESULTS
  We identified 12 mutations in these 7 patients. Three mutations (del245Y in NKCC2, R1009X in NCCT, V524I in ClC-Kb) have not been reported previously. In NKCC2 gene screening, patient A was homozygous for del245Y. In ClC-Kb gene screening, L27R was detected in patients B, D, and E. V524I was detected in patient C. Both T562M and E578K were observed in patients B and E. In NCCT gene screening, patients B-G shared a common novel mutation, R1009X, and patients D, E, F, and G carried this mutation in both alleles. Patients B and C carried R1009X in one allele, and a 6-amino acid insertion in exon 6 and L849H in another allele, respectively. The 4 other mutations did not result in any amino acid exchange. Despite the NCCT gene mutation, patients C and E showed normomagnesemia.
  
  
  CONCLUSIONS
  Our findings demonstrate that in Bartter's and Gitelman's syndromes, it may not be uncommon to see mutations in several causative transporter genes.
authors.affiliation: Department of Pediatrics, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Fukuyama
authors.forename: Shoko
authors.initials: S
authors.lastname: Okudaira
authors.forename: Syosin
authors.initials: S
authors.lastname: Yamazato
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamazato
authors.forename: Takao
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000471:Alkalosis / Q000235:genetics*; D027321:Anion Transport Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D018118:Chloride Channels / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D007008:Hypokalemia / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D049992:Sodium Chloride Symporters; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics*; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters
chemical_list: D027321:Anion Transport Proteins; C412733:CLCNKB protein, human; D002352:Carrier Proteins; D018118:Chloride Channels; C086989:KCNJ1 protein, human; D008565:Membrane Proteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; C578714:SLC12A1 protein, human; C578874:SLC12A3 protein, human; D049992:Sodium Chloride Symporters; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; C064415:thiazide receptor