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.