Mutations in the Human Na-K-2Cl Cotransporter (NKCC2) Identified in Bartter Syndrome Type I Consistently Result in Nonfunctional Transporters

Mutations in the Human Na-K-2Cl Cotransporter (NKCC2) Identified in Bartter Syndrome Type I Consistently Result in Nonfunctional Transporters Abnormalities of the Na-K-Cl Cotransporter in Bartter Syndrome. Bartter syndrome, an inherited disorder of renal NaCl reabsorption, can be caused by mutations of the Na-K-Cl cotransporter (NKCC2), potassium channel (ROMK), chloride channel (ClC-Kb), or Barttin. Mutations of NKCC2 produce a severe neonatal form of Bartter syndrome with polyuria, polyhydramnios, hypokalemic metabolic alkalosis, and hypercalciuria. To determine the effects NKCC2 mutations on the function of the protein, Starremans et al. expressed cRNAs encoding wild-type or mutant NKCC2 in Xenopus oocytes. Surprisingly, they found that injection of identical amounts of cRNA produced significantly lower amounts of mutant protein compared with wild-type. The small amount of mutant protein that was produced was appropriately localized in the plasma membrane but was functionally inactive. In Gitelman syndrome, by contrast, the mutant Na-Cl cotransporter (NCC) is often retained in the endoplasmic reticulum. These studies represent the first functional characterization of NKCC2 mutations in Bartter syndrome. Although the results need to be confirmed in mammalian cells, they suggest that mutations of the NKCC2 gene cause reduced expression and loss of function of the Na-K-Cl cotransporter without affecting trafficking to the plasma membrane.