Hereditary Nephrogenic Diabetes Insipidus in Japanese Patients: Analysis of 78 Families and Report of 22 New Mutations in AVPR2 and AQP2

Background: Familial form of nephrogenic diabetes insipidus (NDI) is a rare hereditary disease caused by arginine vasopressin type 2 receptor (AVPR2) or water channel aquaporin 2 (AQP2) gene mutations. It is speculated that 90% of NDI families carry disease-causing mutations in AVPR2 and 10% carry the mutations in AQP2; however, these percentages have not been supported by actual data. It is also unknown whether these percentages vary in different ethnic groups.

Methods: Gene mutation analyses were performed for 78 Japanese NDI families. All exons and intron-exon boundaries of the AVPR2 and AQP2 genes were directly sequenced.

Results: A total of 62 families (79%) carried disease-causing mutations in AVPR2, while nine families (12%) carried mutations in AQP2. We identified 22 novel putatively disease-causing mutations (19 in AVPR2 and 3 in AQP2). Regarding AVPR2, 52 disease-causing mutations were identified. Among them, missense mutations were most common (54%), followed by deletion mutations. In the 64 women who had monoallelic disease-causing AVPR2 mutations, 16 (25%) had NDI symptoms, including 4 complete NDI subjects. Regarding AQP2, 9 disease-causing mutations were identified in nine families. Two missense mutations and one deletion mutation showed a recessive inheritance, while one missense mutation and five small deletion mutations in the C-terminus of AQP2 showed a dominant inheritance.

Conclusions: Most Japanese NDI families carry disease-causing mutations in AVPR2 and 12% carry mutations in AQP2. A total of 22 novel putatively disease-causing mutations were identified. The relatively high occurrence of symptomatic carriers of AVPR2 mutations needs attention.