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Cell-biologic and functional analyses of five new Aquaporin-2 missense mutations that cause recessive nephrogenic diabetes insipidus

Item Type:Article
Title:Cell-biologic and functional analyses of five new Aquaporin-2 missense mutations that cause recessive nephrogenic diabetes insipidus
Creators Name:Marr, N. and Bichet, D.G. and Hoefs, S. and Savelkoul, P.J. and Konings, I.B. and De Mattia, F. and Graat, M.P. and Arthus, M.F. and Lonergan, M. and Fujiwara, T.M. and Knoers, N.V. and Landau, D. and Balfe, W.J. and Oksche, A. and Rosenthal, W. and Mueller, D. and Van Os, C.H. and Deen, P.M.
Abstract:Mutations in the Aquaporin-2 gene, which encodes a renal water channel, have been shown to cause autosomal nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. Most AQP2 missense mutants in recessive NDI are retained in the endoplasmic reticulum (ER), but AQP2-T125M and AQP2-G175R were reported to be nonfunctional channels unimpaired in their routing to the plasma membrane. In five families, seven novel AQP2 gene mutations were identified and their cell-biologic basis for causing recessive NDI was analyzed. The patients in four families were homozygous for mutations, encoding AQP2-L28P, AQP2-A47V, AQP2-V71M, or AQP2-P185A. Expression in oocytes revealed that all these mutants, and also AQP2-T125M and AQP2-G175R, conferred a reduced water permeability compared with wt-AQP2, which was due to ER retardation. The patient in the fifth family had a G>A nucleotide substitution in the splice donor site of one allele that results in an out-of-frame protein. The other allele has a nucleotide deletion (c652delC) and a missense mutation (V194I). The routing and function of AQP2-V194I in oocytes was not different from wt-AQP2; it was therefore concluded that c652delC, which leads to an out-of-frame protein, is the NDI-causing mutation of the second allele. This study indicates that misfolding and ER retention is the main, and possibly only, cell-biologic basis for recessive NDI caused by missense AQP2 proteins. In addition, the reduced single channel water permeability of AQP2-A47V (40%) and AQP2-T125M (25%) might become of therapeutic value when chemical chaperones can be found that restore their routing to the plasma membrane.
Keywords:Amino Acid Sequence, Aquaporins, Cell Line, Cell Membrane, Diabetes Insipidus, Nephrogenic, Family Health, Recessive Genes, Molecular Sequence Data, Mutation, Missense, Oocytes, Pedigree, Tertiary Protein Structure, Protein Transport, Water, Animals, Frogs
Source:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology (U.S.A.)
Page Range:2267-2277
Date:September 2002
Official Publication:https://doi.org/10.1097/01.ASN.0000027355.41663.14
PubMed:View item in PubMed

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