AN AQUAPORIN-2 WATER CHANNEL MUTANT WHICH CAUSES AUTOSOMAL-DOMINANT NEPHROGENIC DIABETES-INSIPIDUS IS RETAINED IN THE GOLGI-COMPLEX

Mutations in the aquaporin-2 (AQP2) water channel gene cause autosomal recessive nephrogenic diabetes insipidus (NDI), Here we report the fi rst patient with an autosomal dominant form of NDI, which is caused by a G866A transition in the AQP2 gene of one allele, resulting in a E25 8K substitution in the C-tail of AQP2. To define the molecular cause o f NDI in this patient, AQP2-E258K was studied in Xenopus oocytes. In c ontrast to wild-type AQP2, AQP2-E258K conferred a small increase in wa ter permeability, caused by a reduced expression at the plasma membran e. Coexpression of wild-type AQP2 with AQP2-E258K, but not with an AQP 2 mutant in recessive NDI (AQP2-R187C), revealed a dominant-negative e ffect on the water permeability conferred by wild-type AQP2. The physi ologically important phosphorylation of S256 by protein kinase A was n ot affected by the E258K mutation. Immunoblot and microscopic analyses revealed that AQP2-E258K was, in contrast to AQP2 mutants in recessiv e NDI, not retarded in the endoplasmic reticulum, but retained in the Golgi compartment, Since AQPs are thought to tetramerize, the retentio n of AQP2-E258K together with wild-type AQP2 in mixed tetramers in the Golgi compartment is a likely explanation for the dominant inheritanc e of NDI in this patient.