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Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III

Abstract

Analysis of patients with inherited hypokalaemic alkalosis resulting from salt–wasting has proved fertile ground for identification of essential elements of renal salt homeostasis and blood–pressure regulation. We now demonstrate linkage of this phenotype to a segment of chromosome 1 containing the gene encoding a renal chloride channel, CLCNKB. Examination of this gene reveals loss–of–function mutations that impair renal chloride reabsorption in the thick ascending limb of Henle's loop. Mutations in seventeen kindreds have been identified, and they include large deletions and nonsense and missense mutations. Some of the deletions are shown to have arisen by unequal crossing over between CLCNKB and the nearby related gene, CLCNKA. Patients who harbour CLCNKB mutations are characterized by hypokalaemic alkalosis with salt–wasting, low blood pressure, normal magnesium and hyper– or normocalciuria; they define a distinct subset of patients with Bartter's syndrome in whom nephrocalcinosis is absent. These findings demonstrate the critical role of CLCNKB in renal salt reabsorption and blood–pressure homeostasis, and demonstrate the potential role of specific CLCNKB antagonists as diuretic antihypertensive agents.

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References

  1. Lifton, R.P. Molecular genetics of human blood pressure variation. Science 272, 676–680 (1996).

    Article  CAS  Google Scholar 

  2. Bettinelli, A. et al. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J. Pediatr. 120, 38–43 (1992).

    Article  CAS  Google Scholar 

  3. Matsumoto, J. et al. Hypercalciuric Bartter syndrome: resolution of nephrocalcinosis with indomethacin. Am. J. Roentgenol. 152, 1251–1253 (1989).

    Article  CAS  Google Scholar 

  4. Simon, D.B. et al. Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2CI cotransporter NKCC2. Nature Genet. 13, 183–188 (1996).

    Article  CAS  Google Scholar 

  5. Simon, D.B. et al. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nature Genet. 14, 152–156 (1996).

    Article  CAS  Google Scholar 

  6. Reeves, W.B., Winters, C.J., Zimniak, L. & Andreoli, T.E. Epithelial chloride channels, from kidney to airway cells. Adv. Nephol. 23, 177–190 (1994).

    CAS  Google Scholar 

  7. Jorgensen, P.L. Sodium and potassium ion pump in kidney tubules. Physiol. Rev. 60, 864–917 (1980).

    Article  CAS  Google Scholar 

  8. Kieferle, S. et al. Two highly homologous members of the CIC chloride channel family in both rat and human kidney. Proc. Natl. Acad. Sci. USA 91, 6943–6947 (1994).

    Article  CAS  Google Scholar 

  9. Vandewalle, A. et al. Localization and induction by dehydration of CIC-K chloride channels in the rat kidney. Am. J. Physiol. 272, F678–F688 (1995).

    Google Scholar 

  10. Adachi, S. et al. Two isoforms of a chloride channel predominantly expressed in thick ascending limb of Henle's loop and collecting tubules. J. Biol. Chem. 269, 17677–17683 (1994).

    CAS  PubMed  Google Scholar 

  11. Jentsch, T.J. & Günther, W. Chloride channels: an emerging molecular picture. Bioessays 19, 117–126 (1996).

    Article  Google Scholar 

  12. Orita, M. et al. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. Natl. Acad. Sci. USA 86, 2766–2770 (1989).

    Article  CAS  Google Scholar 

  13. Lander, E.S. & Botstein, D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science 236, 1567–1570 (1987).

    Article  CAS  Google Scholar 

  14. Saito-Ohara, F. et al. Assignment of the genes encoding the human chloride channels, CLCNKA and CLCNKB, to 1p36 and of CLCN3 to 4q32–q33 by in situ hybridization. Genomics 36, 372–374 (1996).

    Article  CAS  Google Scholar 

  15. Simon, D.B. et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na–CI cotransporter. Nature Genet. 12, 24–30 (1996).

    Article  CAS  Google Scholar 

  16. Greger, R. & Schlatter, E. Properties of the cortical thick ascending limb of Henle's loop of rabbit kidney: a model of secondary active chloride transport. Pflüngers Arch. 396, 325–334 (1983).

    Article  CAS  Google Scholar 

  17. Lauer, J., Shen, C.K. & Maniatis, T. The chromosomal arrangement of human alpha-like globin genes: sequence homology and alpha-globin gene deletions. Cell 20, 119–130 (1980).

    Article  CAS  Google Scholar 

  18. Nathans, J. et al. Molecular genetics of inherited variation in human color vision. Science 232, 203–210 (1986).

    Article  CAS  Google Scholar 

  19. White, P.C., Vitek, A., Dupont, B. & New, M.I. Characterization of frequent deletions causing steroid 21-hydroxylase deficiency. Proc. Natl. Acad. Sci. USA 85, 4436–4440 (1988).

    Article  CAS  Google Scholar 

  20. Lifton, R.P. et al. A chimaeric 11β-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355, 262–265 (1992).

    Article  CAS  Google Scholar 

  21. Shimkets, R.A. et al. Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell 79, 407–414 (1994).

    Article  CAS  Google Scholar 

  22. Hansson, J.H. et al. Hypertension caused by a truncated epithelial sodium channel subunit: genetic heterogeneity of Liddle syndrome. Nature Genet. 11, 76–82 (1995).

    Article  CAS  Google Scholar 

  23. Chang, S.S. et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nature Genet. 12, 248–253 (1996).

    Article  CAS  Google Scholar 

  24. Lloyd, S.E. et al. A common molecular basis for three inherited kidney stone diseases. Nature 379, 445–449 (1996).

    Article  CAS  Google Scholar 

  25. Bell, G., Karam, J. & Rutter, W. Polymorphic DNA region adjacent to the 5′ end of the human insulin gene. Proc. Natl. Acad. Sci. USA 78, 5759–5763 (1981).

    Article  CAS  Google Scholar 

  26. Gyapay, G. et al. The 1993–94 Généthon human genetic linkage map. Nature Genet. 7, 246–339 (1994).

    Article  CAS  Google Scholar 

  27. Ott, J. Analysis of Human Genetic Linkage (Johns Hopkins University Press, Baltimore, (1985).

    Google Scholar 

  28. Gill, J.R. & Bartter, F.C. Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximate cause of Bartter's syndrome. Am. J. Med. 65, 766–772 (1978).

    Article  CAS  Google Scholar 

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Correspondence to Richard P. Lifton.

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Simon, D., Bindra, R., Mansfield, T. et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet 17, 171–178 (1997). https://doi.org/10.1038/ng1097-171

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