Mutations in the Chloride Channel Gene CLCNKB as a Cause of Classic Bartter Syndrome MARTIN KONRAD,* MARTIN VOLLMER, ² HENNY H. LEMMINK, ‡ LAMBERTUS P. W. J. VAN DEN HEUVEL, ‡ NIKOLA JECK,* ROSA VARGAS-POUSSOU, § ALICIA LAKINGS, i RAINER RUF, ² GEORGES DESCH ˆ ENES, ¶ CORINNE ANTIGNAC, § LISA GUAY-WOODFORD, i NINE V. A. M. KNOERS, ‡ HANNSJ ¨ ORG W. SEYBERTH,* DELPHINE FELDMANN, ¶ and FRIEDHELM HILDEBRANDT ² *Department of Pediatrics, Philipps University, Marburg, Germany; ² Department of Pediatrics, Albert Ludwigs University of Freiburg, Germany; ‡ Departments of Pediatrics and Human Genetics, University Hospital Nijmegen, The Netherlands; § Institut National de la Sante´ et de la Recherche Me´dicale U423, Necker Hospital, University of Paris, France; i Departments of Medicine and Pediatrics, University of Alabama at Birmingham, Alabama; ¶ Departments of Biochemistry and Pediatric Nephrology, Armand-Trousseau Hospital, Paris, France. Abstract. Inherited hypokalemic renal tubulopathies are differ- entiated into at least three clinical subtypes: (1) the Gitelman variant of Bartter syndrome (GS); (2) hyperprostaglandin E syndrome, the antenatal variant of Bartter syndrome (HPS/ aBS); and (3) the classic Bartter syndrome (cBS). Hypokale- mic metabolic alkalosis and renal salt wasting are the common characteristics of all three subtypes. Hypocalciuria and hypo- magnesemia are specific clinical features of Gitelman syn- drome, while HPS/aBS is a life-threatening disorder of the newborn with polyhydramnios, premature delivery, hyposthe- nuria, and nephrocalcinosis. The Gitelman variant is uniformly caused by mutations in the gene for the thiazide-sensitive NaCl-cotransporter NCCT (SLC12A3) of the distal tubule, while HPS/aBS is caused by mutations in the gene for either the furosemide-sensitive NaK-2Cl-cotransporter NKCC2 (SLC12A1) or the inwardly rectifying potassium channel ROMK (KCNJ1). Recently, mutations in a basolateral chloride channel CLC-Kb (CLCNKB) have been described in a subset of patients with a Bartter-like phenotype typically lacking nephrocalcinosis. In this study, the screening for CLCNKB mutations showed 20 different mutations in the affected children from 30 families. The clinical characterization re- vealed a highly variable phenotype ranging from episodes of severe volume depletion and hypokalemia during the neo- natal period to almost asymptomatic patients diagnosed during adolescence. This study adds 16 novel mutations to the nine already described, providing further evidence that mutations in the gene for the basolateral chloride channel CLC-Kb are the molecular basis of classic Bartter syn- drome. Interestingly, the phenotype elicited by CLCNKB mutations occasionally includes HPS/aBS, as well as a Gitelman-like phenotype. Inherited hypokalemic tubulopathies have previously been summarized under the term Bartter syndrome (BS). All disease variants follow autosomal recessive inheritance and share the following characteristic clinical features: renal salt wasting, hypokalemic metabolic alkalosis, normotensive hyperrenine- mic hyperaldosteronism, and hyperplasia of the juxtaglomeru- lar apparatus. Recent identification of the primary genetic defects and extensive pathophysiologic studies have allowed a more stringent molecular genetic classification. However, the correlation between molecular genetic defects and the clinical phenotype has not been clearly delineated as yet. From a clinical perspective, the classification into three different vari- ants seems justified (1,2): 1. In Gitelman syndrome (GS), the hypocalciuric-hypomag- nesemic variant (3), patients are often asymptomatic with the exception of transient muscular weakness, carpopedal spasms, tetanic episodes, and abdominal pain. Therefore, diagnosis is made as a rule after the age of 6 yr. In contrast to the other variants, there is marked hypocalciuria and hypomagnesemia. 2. Hyperprostaglandin E syndrome (HPS), also known as an- tenatal Bartter syndrome (aBS) (1,2,4,5), is the most severe form and leads to polyhydramnios and premature birth due to excessive polyuria in utero. Often there is a life-threat- ening clinical course in the perinatal period with severe salt Received October 18, 1999. Accepted January 18, 2000. Dr. Martin Konrad and Dr. Martin Vollmer contributed equally to this work. Dr. Daniel G. Bichet served as Guest Editor and supervised the review and final disposition of this manuscript. Correspondence to Dr. Hannsjo¨rg W. Seyberth, Department of Pediatrics, Philipps University, Deutschhausstrasse 12, D-35037 Marburg, Germany. Phone: 149 6421 2866226; Fax: 149 6421 2868956; E-mail: seyberth@ mailer.uni-marburg.de 1046-6673/1108-1449 Journal of the American Society of Nephrology Copyright © 2000 by the American Society of Nephrology J Am Soc Nephrol 11: 1449 –1459, 2000