Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response

Congenital nephrogenic diabetes insipidus (NDI) is a rare disease causedmost often by mutations in the vasopressin V2 receptor (AVPR2). We studieda family which included a female patient with NDI with symptoms dating frominfancy. The patient responded to large doses of desmopressin (dDAVP) whichdecreased urine volume from 10 to 4 I/day. Neither the parents nor thethree sisters were polyuric. The patient was found to be a compoundheterozygote for two novel recessive point mutations in the aquaporin-2(AQP2) gene: L22V in exon 1 and C181W in exon 3. Residue Cys181 in AQP2 isthe site for inhibition of water permeation by mercurial compounds and islocated near to the NPA motif conserved in all aquaporins. Osmotic waterpermeability (Pf) in Xenopus oocytes injected with cRNA encoding C181W-AQP2was not increased over water control, while expression of L22V cRNAincreased the Pf to approximately 60% of that for wild-type AQP2.Co-injection of the mutant cRNAs with the wild-type cRNA did not affect thefunction of the wild-type AQP2. Immunolocalization of AQP2-transfected CHOcells showed that the C181W mutant had an endoplasmic reticulum-likeintracellular distribution, whereas L22V and wild-type AQP2 showed endosomeand plasma membrane staining. Water permeability assays showed a high Pf incells expressing wild-type and L22V AQP2. This study indicates that AQP2mutations can confer partially responsive NDI.