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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^* and Peter M. T. Deen^*

Departments of *Cell Physiology and Human Genetics, UMC St. Radboud, Nijmegen, The Netherlands; Department of Medicine, University of Montreal and Centre de Recherches, Hôpital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada; Departments of Human Genetics and Medicine, McGill University and Research Institute of the McGill University Health Centre, Montreal, Canada; ^¶Department of Pediatrics, Soroka Medical Center, Beer Sheva, Israel; ^#Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada; and ^||Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.

Correspondence to Dr. Peter M. T. Deen, 162, Department of Cell Physiology, NCMLS, UMC St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31-24-361-7347; Fax: 31-24-3616430; E-mail: peterd{at}sci.kun.nl

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.

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