Defective processing and trafficking of water channels in nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus (NDI) is a disease characterized by the inab ility of the kidney to concentrate urine upon stimulation with vasopressin. Mutations in the gene for aquaporin-2 (AQP2) are the cause of the autosoma l recessive and autosomal dominant forms of NDI. Mutant AQP2 proteins, foun d in autosomal recessive NDI, were shown to be misfolded and retarded in th e endoplasmic reticulum. One mutant protein leading to autosomal dominant N DI, E258K, has been analyzed in detail. It was shown that this mutant was n ot retarded in the endoplasmic reticulum but mainly retained in the Golgi n etwork. Furthermore, this particular mutant was able to form heterotetramer s with wild-type AQP2, in contrast to mutants found in autosomal recessive NDI. The subsequent misrouting of complexes containing wild-type and mutant AQP2 proteins explains dominant NDI. Copyright (C) 2000 S. Karger AG, Base l.