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Single Amino Acid Substitution in Aquaporin 11 Causes Renal Failure

Elena E. Tchekneva^*, Zaza Khuchua, Linda S. Davis^*, Veronika Kadkina^*, Stephen R. Dunn, Sebastian Bachman, Kenichi Ishibashi^||, Eugene M. Rinchik^¶, Raymond C. Harris^*, Mikhail M. Dikov^** and Matthew D. Breyer^*,

^* Division of Nephrology and ^** Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio; Genomics Facility, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Centrum fur Anatomie, Charite–Universitatsmedizin Berlin, Berlin, Germany; ^|| Department of Medical Physiology, Meiji Pharmaceutical University, Tokyo, Japan; ^¶ Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee; Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee; and Biotechnology Discovery Research, Eli Lilly and Company, Lilly Corporate Centre, Indianapolis, Indiana

Correspondence: Dr. Elena E. Tchekneva, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, 21st Avenue So. at Garland, Nashville, TN 37232. Phone: 615-343-9867; Fax: 615-343-4704; E-mail: elena.tchekneva{at}vanderbilt.edu

Received for publication March 14, 2008. Accepted for publication May 20, 2008.

A screen of recessive mutations generated by the chemical mutagen n-ethyl-n-nitrosourea (ENU) mapped a new mutant locus (5772SB) termed sudden juvenile death syndrome (sjds) to chromosome 7 in mice. These mutant mice, which exhibit severe proximal tubule injury and formation of giant vacuoles in the renal cortex, die from renal failure, a phenotype that resembles aquaporin 11 (Aqp11) knockout mice. In this report, the ENU-induced single-nucleotide variant (sjds mutation) is identified. To determine whether this variant, which causes an amino acid substitution (Cys227Ser) in the predicted E-loop region of aquaporin 11, is responsible for the sjds lethal renal phenotype, Aqp11^–/sjds compound heterozygous mice were generated from Aqp11^+/sjds and Aqp11^+/– intercrosses. The compound heterozygous Aqp11^–/sjds offspring exhibited a lethal renal phenotype (renal failure by 2 wk), similar to the Aqp11^sjds/sjds and Aqp11^–/– phenotypes. These results demonstrate that the identified mutation causes renal failure in Aqp11^sjds/sjds mutant mice, providing a model for better understanding of the structure and function of aquaporin 11 in renal physiology.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673