title: Single amino acid substitution in aquaporin 11 causes renal failure.
abstract: 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.
authors.affiliation: Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. elena.tchekneva@vanderbilt.edu
authors.forename: Elena E
authors.initials: EE
authors.lastname: Tchekneva
authors.forename: Zaza
authors.initials: Z
authors.lastname: Khuchua
authors.forename: Linda S
authors.initials: LS
authors.lastname: Davis
authors.forename: Veronika
authors.initials: V
authors.lastname: Kadkina
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Dunn
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachman
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishibashi
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Rinchik
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Dikov
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D020346:Aquaporins / Q000235:genetics*; D004195:Disease Models, Animal; D005038:Ethylnitrosourea; D005260:Female; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D017354:Point Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051437:Renal Insufficiency / Q000235:genetics*; D013577:Syndrome
chemical_list: C503878:Aqp11 protein, mouse; D020346:Aquaporins; D005038:Ethylnitrosourea