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. Abbreviations GS, Gitelman syndrome cBS, classic Bartter syndrome DCT, distal convoluted tubule NCCT, thiazide-sensitive NaCl cotransporter ClC-Kb, kidney-specific basolateral chloride channel TAL, thick ascending limb of Henle's loop HPS/aBS, hyperprostaglandin E/antenatal Bartter syndrome GS (MIM 263800) is an inherited renal tubular disorder characterized by impaired conservation of potassium and magnesium (1). The mode of inheritance is autosomal-recessive. The first clinical presentation is usually observed during childhood or adolescence and may include transient episodes of weakness, paresthesia, and tetany. The course of disease is generally mild and some patients even remain asymptomatic (2, 3, 4). GS patients share several biochemical findings with the more severe cBS, such as hypokalemia, metabolic alkalosis, and elevated plasma aldosterone levels (5). However, the coexistence of hypomagnesemia and hypocalciuria is considered a pathognomonic laboratory finding in GS that allows the differentiation from cBS (6).Both the observation that the electrolyte disturbances in GS resemble the effect of chronic thiazide administration (7, 8) and the results of clearance studies have pointed to a defect in the distal thiazide-sensitive sodium chloride transport (9). This hypothesis has been substantiated by the demonstration that GS is caused by mutations in the SLC12A3 gene, which encodes the NCCT of the DCT (10). Meanwhile, more than 100 mutations throughout the NCCT have been described in GS patients, sugge...

Clinical and Genetic Spectrum of Bartter Syndrome Type 3

“…24 We found a downward shift of the relationship between plasma chloride and sodium 25 concentrations consistent with a defect in adaptation to chloride depletion in BS3 as compared 1 to BS1 and BS2 patients. These results are consistent with the phenotype of mice with Clcnk2 2 disruption 27 and suggest that sodium and potassium supplementation should be provided as 3 chloride salts in BS3 patients. 4 Third, nineteen patients presented CKD, and seven of these patients also had proteinuria 5 ( Table 4).…”

“…Five CBS patients required 2 psychiatric follow-up (hyperactivity, anorexia, or eating disorders). 3 Irregular heart rate or ECG abnormalities were documented in six patients: one A/NBS patient 4 had premature ventricular beats with prolonged QT interval, three CBS patients had a right 5 bundle branch block or U wave, and one GLS patient presented torsade de pointe attacks. 6 None of the patients in this cohort had high blood pressure.…”

Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders

“…In addition, GS patients virtually always have hypocalciuria. The presence of both hypomagnesemia and hypocalciuria is highly predictive for the diagnosis of GS (89) even if in rare cases this combination is also detected in cBS patients (90). GS is often described as the mild variant of the salt-losing tubular disorders, and many asymptomatic patients have been reported.…”

Simultaneous Mutations in the CLCNKB and SLC12A3 Genes in Two Siblings with Phenotypic Heterogeneity in Classic Bartter Syndrome

“…Jeck subsequently reported three unrelated patients with CLCNKB gene mutations and a phenotype transition from cBS to GS (13), and Zelikovic demonstrated the simultaneous presence of both cBS and GS phenotypes in a wide sibship carrying the same CLCNKB mutation (14). However, the simultaneous presence of SLC12A3 and CLCNKB gene mutations has never been reported.…”