Hereditary nephrogenic diabetes insipidus in Japanese patients: Analysis of 78 families and report of 22 new mutations in AVPR2 and AQP2

Abstract

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. © 2012 Japanese Society of Nephrology.