NOVEL MUTATIONS IN AQUAPORIN-2 GENE IN FEMALE SIBLINGS WITH NEPHROGENIC DIABETES-INSIPIDUS - EVIDENCE OF DISRUPTED WATER CHANNEL FUNCTION

Novel mutations of the aquaporin-2 (AQP2) gene have been detected in J apanese female siblings with autosomal-recessive nephrogenic diabetes insipidus. The patients were compound heterozygote for point mutations at nucleotide position 374 (C374T) and at position 523 (G523A) in exo n 2 of the AQP2 gene, resulting in substitution of methionine for thre onine at codon 125 (T125M) and arginine for glycine at codon 175 (G175 R). The water permeability (Pf) of oocytes injected with wild-type com plementary RNA increased 9.0-fold compared with the Pf of water-inject ed oocytes, whereas the increases in the Pf of oocytes injected with T 125M and G175R complementary RNA were only 1.7-fold and 1.5-fold, resp ectively. Immunoblot and immunocytochemistry indicated that the plasma membrane expressions of T125M and G175R AQP2 proteins were comparable to that of the wild-type, suggesting that although neither the T125M nor G175R mutation had a significant effect on plasma membrane express ion, they both distorted the structure and function of the aqueous por e of AQP2. These results provide evidence that the nephrogenic diabete s insipidus in patients with T125M and G175R mutations is attributable not to the misrouting of AQP2, but to the disrupted water channel fun ction.