Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III (original) (raw)

• Article
• Published: 01 October 1997
• Ranjit S. Bindra1,
• Traci A. Mansfield1,
• Carol Nelson-Williams1,
• Erica Mendonca2,
• Rosário Stone2,
• Scott Schurman3,
• Ahmet Nayir4,
• Harika Alpay4,
• Aysin Bakkaloglu5,
• Juan Rodriguez-Soriano6,
• Jose M. Morales7,
• Sami A. Sanjad8,
• C. Mark Taylor9,
• Daniela Pilz10,
• Andrew Brem11,
• Howard Trachtman12,
• William Griswold13,
• George A. Richard14,
• Eunice John15 &
• …
• Richard P. Lifton1

Nature Genetics volume 17, pages 171–178 (1997)Cite this article

• 1741 Accesses
• 9 Altmetric
• Metrics details

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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

• Purchase on SpringerLink
• Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

• Log in
• Learn about institutional subscriptions
• Read our FAQs
• Contact customer support

Similar content being viewed by others

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

Download references

Author information

Authors and Affiliations

1. Howard Hughes Medical Institute, Departments of Medicine and Genetics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, 06510, USA
   David B. Simon, Ranjit S. Bindra, Traci A. Mansfield, Carol Nelson-Williams & Richard P. Lifton
2. Unidade de Nefrologia Pediátrica, Hospital de Santa Maria, Lisbon, Portugal
   Erica Mendonca & Rosário Stone
3. Department of Pediatrics, All Children's Hospital, St. Petersburg, Florida, 33701, USA
   Scott Schurman
4. Department of Pediatric Nephrology, University of Istanbul, Istanbul, Turkey
   Ahmet Nayir & Harika Alpay
5. Department of Pediatric Nephrology, Hacettepe University, Children's Hospital, Ankara, Turkey
   Aysin Bakkaloglu
6. Department of Pediatrics, Hospital de Cruces, Baracaldo, Spain
   Juan Rodriguez-Soriano
7. Department of Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain
   Jose M. Morales
8. Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
   Sami A. Sanjad
9. Department of Nephrology, Birmingham Children's Hospital, Ladywood, Birmingham, B16 SET, UK
   C. Mark Taylor
10. Institute of Medical Genetics, University Hospital of Wales, Cardiff, CF4 4XW, Wales, UK
    Daniela Pilz
11. Department of Pediatric Nephrology, Rhode Island Hospital, Providence, Rhode Island, 02903, USA
    Andrew Brem
12. Department of Pediatrics, Albert Einstein College of Medicine, Schneider Children's Hospital, New Hyde Park, New York, 11040-1432, USA
    Howard Trachtman
13. Department of Pediatrics, Children's Hospital of San Diego, San Diego, California, 92123, USA
    William Griswold
14. Department of Pediatrics, University of Florida, Gainsville, Florida, 32610, USA
    George A. Richard
15. Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, 60612, USA
    Eunice John

Authors

1. David B. Simon
   You can also search for this author inPubMed Google Scholar
2. Ranjit S. Bindra
   You can also search for this author inPubMed Google Scholar
3. Traci A. Mansfield
   You can also search for this author inPubMed Google Scholar
4. Carol Nelson-Williams
   You can also search for this author inPubMed Google Scholar
5. Erica Mendonca
   You can also search for this author inPubMed Google Scholar
6. Rosário Stone
   You can also search for this author inPubMed Google Scholar
7. Scott Schurman
   You can also search for this author inPubMed Google Scholar
8. Ahmet Nayir
   You can also search for this author inPubMed Google Scholar
9. Harika Alpay
   You can also search for this author inPubMed Google Scholar
10. Aysin Bakkaloglu
    You can also search for this author inPubMed Google Scholar
11. Juan Rodriguez-Soriano
    You can also search for this author inPubMed Google Scholar
12. Jose M. Morales
    You can also search for this author inPubMed Google Scholar
13. Sami A. Sanjad
    You can also search for this author inPubMed Google Scholar
14. C. Mark Taylor
    You can also search for this author inPubMed Google Scholar
15. Daniela Pilz
    You can also search for this author inPubMed Google Scholar
16. Andrew Brem
    You can also search for this author inPubMed Google Scholar
17. Howard Trachtman
    You can also search for this author inPubMed Google Scholar
18. William Griswold
    You can also search for this author inPubMed Google Scholar
19. George A. Richard
    You can also search for this author inPubMed Google Scholar
20. Eunice John
    You can also search for this author inPubMed Google Scholar
21. Richard P. Lifton
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toRichard P. Lifton.

Rights and permissions

About this article

Cite this article

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

Download citation

• Received: 15 July 1997
• Accepted: 15 August 1997
• Issue Date: 01 October 1997
• DOI: https://doi.org/10.1038/ng1097-171