title: Functional Recovery of AQP2 Recessive Mutations Through Hetero-Oligomerization with Wild-Type Counterpart.
abstract: Aquaporin-2 (AQP2) is a homotetrameric water channel responsible for the final water reuptake in the kidney. Mutations in the protein induce nephrogenic diabetes insipidus (NDI), which challenges the water balance by producing large urinary volumes. Although recessive AQP2 mutations are believed to generate non-functional and monomeric proteins, the literature identifies several mild mutations which suggest the existence of mixed wt/mut tetramers likely to carry function in heterozygotes. Using Xenopus oocytes, we tested this hypothesis and found that mild mutants (V24A, D150E) can associate with wt-AQP2 in mixed heteromers, providing clear functional gain in the process (62 ± 17% and 63 ± 17% increases, respectively), conversely to the strong monomeric R187C mutant which fails to associate with wt-AQP2. In kidney cells, both V24A and D150E display restored targeting while R187C remains in intracellular stores. Using a collection of mutations to expand recovery analyses, we demonstrate that inter-unit contacts are central to this recovery process. These results not only present the ground data for the functional recovery of recessive AQP2 mutants through heteromerization, which prompt to revisit the accepted NDI model, but more importantly describe a general recovery process that could impact on all multimeric systems where recessive mutations are found.
authors.affiliation: Groupe d'Étude des Protéines Membranaires (GÉPROM), département de Physiologie moléculaire et intégrative, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Abdulah
authors.initials: A
authors.lastname: El Tarazi
authors.affiliation: Groupe d'Étude des Protéines Membranaires (GÉPROM), département de Physiologie moléculaire et intégrative, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Lussier
authors.affiliation: Groupe d'Étude des Protéines Membranaires (GÉPROM), département de Physiologie moléculaire et intégrative, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Da Cal
authors.affiliation: Groupe d'Étude des Protéines Membranaires (GÉPROM), département de Physiologie moléculaire et intégrative, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bissonnette
authors.affiliation: Groupe d'Étude des Protéines Membranaires (GÉPROM), département de Physiologie moléculaire et intégrative, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada.|Centre de Recherche, Hôpital du Sacré-Cœur de Montréal, Montréal, Québec, H4J 1C5, Canada.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D055503:Protein Multimerization; D014867:Water / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D051399:Aquaporin 2; D014867:Water