56C>T A19V Recessive New   c.85G>A G29S Recessive Sahakitrungruang et al. [26]   c.761G>A R254Q Dominant Savelkoul et al. [28]  Deletion mutations   c.127_128delCA FS/105X Recessive Tajima et al. [27]   c.750delG FS/334X Dominant New   c.775delC FS/334X Dominant New Previously analyzed  Deletion mutations   c.721delG FS/334X Dominant Kuwahara et al. [12]   c.763–772del

FS/331X Dominant Kuwahara et al. [12]   c.812–818del FS/332X Dominant Kuwahara et al. [12] The family trees and results of mutation analysis of newly analyzed families are summarized in Fig. 1. In family 1, two missense mutations (A19V and G29S) were compound heterozygous in a male NDI Selleck RAD001 patient and manifested by vasopressin-unresponsive polyuria (8–10 L/day). The patient’s

parents were asymptomatic. The father carried a novel A19V mutation, while the mother had a G29S mutation, which was previously reported to be causative [26]. In family 2, the G29S mutation (the same one found in family 1) was homozygous in the proband, and his healthy mother and brother were heterozygous for the mutation. The patient 5-Fluoracil manufacturer exhibited polyuria (urine volume was 10–15 L/day), and the urine osmolality did not respond to vasopressin (maximum urine osmolality was about 100 mOsm/L). The appearance of NDI symptoms only when the mutations are compound heterozygous or homozygous strongly indicates that these two missense mutations are disease causative. Fig. 1 AOP2 mutations newly found in Japanese NDI families. Six different AQP2 mutations were found in six Japanese NDI families. NA gene analysis not available. *Showing NDI symptoms In family 3, a homozygous 2-nucleotide deletion mutation (c.127_128delCA) was found in a neonatal boy who exhibited polyuria and dehydration. His urine osmolality did not respond to vasopressin (< 150 mOsm/L). the The resultant frame shift predicts new amino acids starting at codon 43, with a premature stop at codon 105. The same mutation was found in an unrelated Japanese family and has been reported by others [27]. In family

4, a monoallelic R254Q mutation was found in two siblings and their father. The father and paternal relatives had NDI symptoms, but have not been clinically examined. The siblings (a 1-year-old boy and a 3-year-old girl) showed similar clinical characteristics of polyuria and polydipsia starting 4–6 months after birth, and slight responsiveness of urine osmolality to vasopressin (maximum urine osmolality was about 500 mOsm/L after vasopressin administration). Consistent with these observation, this mutation (R254Q) was recently reported as an NDI causative mutation with dominant inheritance [28]. Another missense mutation on this residue, R254L, was also reported to cause a similar NDI phenotype [29].