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Gitelman's variant of Barter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na–Cl cotransporter

Nature Genetics volume 12, pages 24–30 (1996)Cite this article

Abstract

Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function. Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelman's syndrome to the locus encoding the renal thiazide-sensitive Na–Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects. These findings demonstrate the molecular basis of Gitelman's syndrome. We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.

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Author notes

  1. Richard P. Lifton: Correspondence should be addressed to R.P.L.

Authors and Affiliations

  1. Howard Hughes Medical Institute, Department of Genetics, Boyer Center for Molecular Medicine, New Haven, Connecticut, 06510, USA

    David B. Simon, Carol Nelson-Williams, Fiona E. Karet & Richard P. Lifton

  2. Section of Nephrology, Department of Medicine, New Haven, Connecticut, 06510, USA

    David B. Simon, Carol Nelson-Williams, Margaret Johnson Bia, David Ellison, Fiona E. Karet & Richard P. Lifton

  3. West Haven Veteran's Administration Hospital, Yale University School of Medicine, New Haven, Connecticut, 06510, USA

    David Ellison

  4. Servicio de Nefrología, Hospital Son Dureta, Andrea Doria 55, Palma de Mallorca, 07014, Spain

    Antonio Morey Molina

  5. Department of Clinical Chemistry, County Hospital of Växjö, Växjö, S-351 85, Sweden

    Ivar Vaara

  6. Department of Pediatrics, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo, 173, Japan

    Fujihiko Iwata

  7. Department of Medicine, Madigan Army Medical Center, Tacoma, Washington, 98431-5000

    Howard M. Cushner

  8. Bosch Medicentrum, Locatie Groof Ziekengasthius, Postbus 90153, 5200, ME's-Hertogenbosch, The Netherlands

    Marianne Koolen

  9. Servicio de Nefrología, Hospital de Cruces, Baracaldo, Vizcaya, 48903, Spain

    Francisco J. Gainza

  10. Division of Nephrology, UNC School of Medicine, Chapel Hill, North Carolina, 27599-7155

    Hillel J. Gitelman

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Simon, D., Nelson-Williams, C., Johnson Bia, M. et al. Gitelman's variant of Barter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na–Cl cotransporter. Nat Genet 12, 24–30 (1996). https://doi.org/10.1038/ng0196-24

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