Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome

Inherited hypokalemic renal tubulopathies are differentiated into at least three clinical subtypes: (1) the Gitelman variant of Bartter syndrome (GS); (2) hyperprostaglandin E syndrome, the antenatal variant of Bartter syndro me (HPS/ aBS); and (3) the classic Bartter syndrome (cBS). Hypokalemic meta bolic alkalosis and renal salt wasting are the common characteristics of al l three subtypes. Hypocalciuria and hypomagnesemia are specific clinical fe atures of Gitelman syndrome, while HPS/aBS is a life-threatening disorder o f the newborn with polyhydramnios, premature delivery, hyposthenuria, and n ephrocalcinosis, The Gitelman variant is uniformly caused by mutations in t he 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 inwa rdly rectifying potassium channel ROMK (KCNJ1), Recently, mutations in a ba solateral chloride channel CLC-Kb (CLCNKB) have been described in a subset of patients with a Bartter-like phenotype typically lacking nephrocalcinosi s. In this study, the screening for CLCNKB mutations showed 20 different mu tations in the affected children from 30 families. The clinical characteriz ation revealed a highly variable phenotype ranging from episodes of severe volume depletion and hypokalemia during the neonatal period to almost asymp tomatic patients diagnosed during adolescence. This study adds 16 novel mut ations to the nine already described, providing further evidence that mutat ions in the gene for the basolateral chloride channel CLC-Kb are the molecu lar basis of classic Bartter syndrome. Interestingly, the phenotype elicite d by CLCNKB mutations occasionally includes HPS/aBS, as well as a Gitelman- like phenotype.