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

Nannette Marr, Daniel G Bichet, Susan Hoefs, Paul J M Savelkoul, Irene B M Konings, Fabrizio De Mattia, Michael P J Graat, Marie-Françoise Arthus, Michele Lonergan, T Mary Fujiwara, Nine V A M Knoers, Daniel Landau, William J Balfe, Alexander Oksche, Walter Rosenthal, Dominik Müller, Carel H Van Os, Peter M T Deen

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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.

Original languageEnglish
Pages (from-to)2267-77
Number of pages11
JournalJournal of the American Society of Nephrology
Issue number9
Publication statusPublished - Sep-2002
Externally publishedYes


  • Amino Acid Sequence
  • Animals
  • Aquaporin 2
  • Aquaporin 6
  • Aquaporins/chemistry
  • Cell Line
  • Cell Membrane/metabolism
  • Diabetes Insipidus, Nephrogenic/genetics
  • Family Health
  • Female
  • Genes, Recessive
  • Humans
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Mutation, Missense
  • Oocytes/metabolism
  • Pedigree
  • Protein Structure, Tertiary
  • Protein Transport/genetics
  • Water/metabolism
  • Xenopus

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