title: Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter-Gitelman phenotype.
abstract: Gitelman syndrome is an inherited renal disorder characterized by impaired NaCl reabsorption in the distal convoluted tubule and secondary hypokalemic alkalosis. In clinical practice, it is distinguished from other hypokalemic tubulopathies by the presence of both hypomagnesemia and normocalcemic hypocalciuria. To date, only mutations in a single gene encoding the thiazide-sensitive NaCl cotransporter have been found as the molecular basis of GS. We describe three unrelated patients presenting with the typical laboratory findings of GS. Mutational analysis in these patients revealed no abnormality in the SLC12A3 gene. Instead, all patients were found to carry previously described mutations in the CLCNKB gene, which encodes the kidney-specific chloride channel ClC-Kb, raising the possibility of genetic heterogeneity. Review of the medical histories revealed manifestation of the disease within the first year of life in all cases. Clinical presentation included episodes of dehydration, weakness, and failure to thrive, much more suggestive of classic Bartter syndrome than of GS. The coexistence of hypomagnesemia and hypocalciuria was not present from the beginning. In the follow-up, however, a drop of both parameters below normal range was a consistent finding reflecting a transition from cBS to GS phenotype. The phenotypic overlap may indicate a physiologic cooperation of the apical thiazide-sensitive NaCl cotransporter and the basolateral chloride channel for salt reabsorption in the distal convoluted tubule.
authors: Department of Pediatrics, Philipps University, D-35037 Marburg, Germany.
authors: N
authors: N
authors: Jeck
authors: M
authors: M
authors: Konrad
authors: M
authors: M
authors: Peters
authors: S
authors: S
authors: Weber
authors: K E
authors: KE
authors: Bonzel
authors: H W
authors: HW
authors: Seyberth
mesh_terms: D000471:Alkalosis / Q000235:genetics*; D027321:Anion Transport Proteins; D001477:Bartter Syndrome / Q000235:genetics*; D002118:Calcium / Q000652:urine; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D018740:Genetic Heterogeneity; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007008:Hypokalemia / Q000235:genetics*; D017136:Ion Transport / Q000235:genetics*; D007686:Kidney Tubules, Distal / Q000378:metabolism* / Q000473:pathology; D008274:Magnesium / Q000097:blood; D008297:Male; D008565:Membrane Proteins; D010375:Pedigree; D010641:Phenotype; D012964:Sodium / Q000378:metabolism; D013577:Syndrome
chemical_list: D027321:Anion Transport Proteins; C412733:CLCNKB protein, human; D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D012964:Sodium; D008274:Magnesium; D002118:Calcium