Salt Wasting and Deafness Resulting from Mutations in Two Chloride Channels

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Abstract
Inherited kidney disorders associated with salt wasting, hypokalemia, and metabolic alkalosis (Bartter's syndrome) are clinically classified into several variants1: classic Bartter's syndrome,2 Gitelman's variant of Bartter's syndrome,3 and antenatal Bartter's syndrome (originally described as the hyperprostaglandin E syndrome).4 The classic form and Gitelman's variant are characteristically accompanied by hypokalemia during early infancy or adolescence, whereas the antenatal form is marked by polyhydramnios in the mother, followed by severe volume depletion in the infant during the early neonatal period. Molecular genetic analyses of the different forms of Bartter's syndrome have revealed mutations in various genes encoding ion channels and transporters that mediate transepithelial salt reabsorption along distal nephron segments: the sodium–potassium–chloride cotransporter NKCC25 and the potassium channel ROMK6 in antenatal Bartter's syndrome (genetically defined as Bartter's types I and II, respectively); the chloride channel ClC-Kb in classic Bartter's syndrome (Bartter's type III)7; and the sodium–chloride cotransporter (NCCT)8 in Gitelman's variant.