ABSTRACT.: 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 syndrome (HPS/aBS); and (3) the classic
Bartter syndrome (cBS). Hypokalemic metabolic
alkalosis and renal
salt wasting are the common characteristics of all three subtypes. Hypocalciuria and hypomagnesemia are specific clinical features of
Gitelman syndrome, while HPS/aBS is a life-threatening disorder of the newborn with
polyhydramnios, premature delivery, hyposthenuria, 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 revealed a highly variable phenotype ranging from episodes of severe volume depletion and
hypokalemia during the neonatal 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 syndrome. Interestingly, the phenotype elicited by CLCNKB mutations occasionally includes HPS/aBS, as well as a Gitelman-like phenotype.