Nature Genetics
17, 171 - 178 (1997)
doi:10.1038/ng1097-171
Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type IIIDavid B. Simon1, 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, 16
1Howard Hughes Medical Institute, Departments of Medicine and Genetics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
2Unidade de Nefrologia Pediátrica, Hospital de Santa Maria, Lisbon, Portugal.
3Department of Pediatrics, All Children's Hospital, St. Petersburg, Florida 33701, USA.
4Department of Pediatric Nephrology, University of Istanbul, Istanbul, Turkey.
5Department of Pediatric Nephrology, Hacettepe University, Children's Hospital, Ankara, Turkey.
6Department of Pediatrics, Hospital de Cruces, Baracaldo, Spain.
7Department of Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain.
8Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
9Department of Nephrology, Birmingham Children's Hospital, Ladywood, Birmingham B16 SET, UK.
10Institute of Medical Genetics, University Hospital of Wales, Cardiff CF4 4XW, Wales, UK.
11Department of Pediatric Nephrology, Rhode Island Hospital, Providence, Rhode Island 02903, USA.
12Department of Pediatrics, Albert Einstein College of Medicine, Schneider Children's Hospital, New Hyde Park, New York 11040-1432, USA.
13Department of Pediatrics, Children's Hospital of San Diego, San Diego, California 92123, USA.
14Department of Pediatrics, University of Florida, Gainsville, Florida 32610, USA.
15Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
16e-mail richard_lifton@qm.yale.edu. 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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