Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families

X-Linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by the excretion of abnormal large volumes of diluted urine m ainly caused by mutations in the V2 vasopressin receptor (AVPR2) gene. By s creening NDT patients for mutations within the AVPR2 gene we have identifie d three novel (I46K, F105V, I130F) and four recurrent (D85N, R106C, R113W, Q225X) mutations. In addition, a recurrent missense mutation (A147T) within the aquaporin-2 gene was identified in a female patient with autosomal rec essive NDI associated with sensorineural deafness. Selected clinical data o f the NDI patients were compared with the results from the in vitro studies . Functional analysis of I46K and I130F revealed reduced maximum agonist-in duced cAMP responses as a result of an improper cell surface targeting. In contrast, the F105V mutation is delivered to the cell surface and displayed an unchanged maximum cAMP response, but impaired ligand binding abilities of F105V were reflected in a shifted concentration-response curve toward hi gher vasopressin concentrations. ils the extracellularly located F105 is hi ghly conserved among the vasopressin/oxytocin receptor family, functional a nalysis of this residue implicates an important role in high affinity agoni st binding.