In nephrogenic diabetes insipidus, the kidney is unable to concentrate urine, despite normal or elevated concentrations of the antidiuretic hormone, arginine vasopressinJ In congenital nephrogenic diabetes insipidus, the obvious clinical manifestations of the disease, polyuria and polydipsia, are present at birth, and need to be immediately recognized to avoid severe episodes of dehydration. Most (> 90%) patients with congenital nephrogenic diabetes insipidus have mutations in theAVPR2 gene that codes for the vasopressin V 2 (antidiuretic) receptor and is located in chromosome region Xq28. 2 In less than 10% of the families studied, congenital nephrogenic diabetes insipidus has an autosomal recessive mode of inheritance, and mutations have been identiffed in the aquaporin-2 gene (AQP2) located in chromosome region 12q13, that codes for the vasopressin-sensitive water channel/Reports of 85 different putative disease-causing mutations in the AVPR2 gene, in 123 unrelated families with X-linked nephrogenic diabetes insipidus, have now been published (Table 1). Of these, 19 disease-causing mutations were identified in ancestrally independent Japanese families. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellularly, and that are unable to reach the plasma membrane. A minority of the mutant receptors reach the cell surface, but are unable to bind arginine vasopressin, or to trigger an intracellular cyclic adenosine monophosphate (cAMP) signal. Similarly, AQP2 mutant proteins are trapped intracellularly, and cannot be expressed at