1998 Global Conference Proceeding

March 02 - 04, 1998

Line
Conference: 1998 Global Conference
Title: Nephrogenic Diabetes Insipidus Patients in Japan
Authors: Sasaki, Sei; Kuwahara, Michio; Ishibashi, Kenichi; Uchida, Shinichi; Bichet, Daniel G.; Marumo, MD, Fumiaki
Institutions: Tokyo Medical & Dental University, Tokyo Medical and Dental University, Medical Research Institute, Graduate School, Tokyo Medical and Dental University School of Medicine, Hopital du Sacre-Coeur de Montreal
Line
Abstract • Translation
Blood samples from 8 different NDI families have been referred to us for genetic and functional analysis. Three families showing X-linked inheritance were proven to have mutations in the V2 receptor gene. The mutations were V88L, R137H, and S127F, of which the former two have been reported previously by others. S127F is a new mutation never described before.

The remaining 5 families showing non-X-linked inheritance were analyzed for AQP2 mutations. Two families were identified to have mutations in this gene. In one family, female siblings presented NDI and were compound heterozygote of two new mutations, T125M and G175R. The parents were carriers of each mutations. In vitro expression studies in the Xenopus oocytes showed that although mutant proteins were expressed in the surface plasma membrane, water permeability of the oocytes was not stimulated by these mutants. This result indicates that these 2 mutations cause a loss of water pore function rather than misrouting of the protein in the oocytes. In another family, a 2 year-old boy showed a clinical presentation of partial DI with urine osmolality of 468 mOsm after 8 hr dehydration. Maximal urine osmolality after dDAVP administration was 551 mOsm. A frameshift mutation was found in the C-terminal which predicts the addition of extra amino acids in the C-terminal.

The remaining 3 families, showing autosomal dominant inheritance pattern, were free of mutations in the AQP2 gene, indicating that we have to consider other genes for their NDI. Speculation about the possible candidate genes for NDI, for example, other AQPs, urea transporters, and chloride channels will be discussed.

Sasaki, et al., studied blood samples of eight Japanese families with cases of nephrogenic diabetes insipidus (NDI) to determine the genetic bases and functional characteristics of each family's NDI. Three families showed X-linked NDI. As expected, each family showed mutations in the V2 receptor gene; however, the mutation was different in each of the three families (one never having been previously described in the research literature). The remaining five families showed non-X-linked NDI. They were analyzed for mutations in a different place, namely the genes in the water-transporting proteins called aquaporins (AQP2). Two of the families had mutations in the AQP2 gene. In one family, it was the daughters who had NDI. These females had a combination of two new mutations carried by their parents. These two mutations disallowed water permeability across membranes. In the fifth family, a two-year-old boy expressed NDI. He had a type of mutation called a frameshift mutation that results in a completely different set of amino acids being made into a protein than required. The remaining three families had no mutations in the AQP2 gene, and, since they showed non-X-linked inheritance of NDI, they had no mutations in the V2 receptor gene. This indicates that NDI researchers will have to consider mutations in other genes, such as urea transporters, chloride channels and other AQPs.