title: A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes.
abstract: BACKGROUND
  Gitelman syndrome (GS) and Bartter syndrome (BS) are hereditary hypokalemic tubulopathies with distinct phenotypic features. GS has been considered a genetically homogeneous disorder caused by mutation in the gene encoding the NaCl cotransporter (TSC) of the distal convoluted tubule. In contrast, BS is caused by mutations in the genes encoding either the Na-K-2Cl cotransporter (NKCC2), the K+ channel (ROMK) or the Cl- channel (ClC-Kb) of the thick ascending limb. The purpose of this study was to examine the clinical, biochemical and genetic characteristics of a very large inbred Bedouin kindred in Northern Israel with hereditary hypokalemic tubulopathy.
  
  
  METHODS
  Twelve family members affected with hypokalemic tubulopathy, as well as 26 close relatives were clinically and biochemically evaluated. All study participants underwent genetic linkage analysis. Mutation analysis was performed in affected individuals.
  
  
  RESULTS
  Evaluation of affected family members (age range 3 to 36 years) revealed phenotypic features of both GS and classic Bartter syndrome (CBS). Features typical of GS included late age of presentation (>15 years) in 7 patients (58%), normal growth in 9 (75%), hypomagnesemia (SMg <0.7mmol/L) in 5 (42%), hypermagnesiuria (FEMg>5%) in 6 (50%) and hypocalciuria (urinary calcium/creatinine mmol/mmol <0.15) in 5 (42%). Features typical of CBS included early age of presentation (<1 year) in 3 (25%), polyuria/dehydration in 4 (33%), growth retardation in 3 (25%), hypercalciuria (urinary calcium/creatinine mmol/mmoverline>0.55) in 4 (33%) and nephrolithiasis in 1 (8%). Linkage analysis in affected patients excluded the TSC gene, SLC12A3, as the mutated gene, but demonstrated linkage to the Cl- channel gene, CLCNKB, on chromosome 1p36. Mutation analysis by direct sequencing revealed a novel homozygous missense mutation, arginine 438 to histidine (R438H), in exon 13 of CLCNKB in all patients. A restriction fragment length polymorphism (RFLP) analysis has been developed to aid in genotyping of family members.
  
  
  CONCLUSIONS
  Our findings demonstrate intrafamilial heterogeneity, namely the presence of GS and CBS phenotypes, in a kindred with the CLCNKB R438H mutation. We conclude that GS can be caused by a mutation in a gene other than SLC12A3. The exact role of the CLCNKB R438H mutation in the pathogenesis of the electrolyte and mineral abnormalities in GS and CBS remains to be established.
authors.affiliation: Department of Nephrology, Rambam Medical Center, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. i_zelikovic@rambam.health.gov.il
authors.forename: Israel
authors.initials: I
authors.lastname: Zelikovic
authors.forename: Raymonde
authors.initials: R
authors.lastname: Szargel
authors.forename: Ali
authors.initials: A
authors.lastname: Hawash
authors.forename: Valentina
authors.initials: V
authors.lastname: Labay
authors.forename: Ihab
authors.initials: I
authors.lastname: Hatib
authors.forename: Nadine
authors.initials: N
authors.lastname: Cohen
authors.forename: Farid
authors.initials: F
authors.lastname: Nakhoul
mesh_terms: D000328:Adult; D027321:Anion Transport Proteins; D018912:Arabs / Q000235:genetics*; D001477:Bartter Syndrome / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007557:Israel; D008297:Male; D008565:Membrane Proteins; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D027321:Anion Transport Proteins; C412733:CLCNKB protein, human; D018118:Chloride Channels; D008565:Membrane Proteins