title: A novel mechanism in recessive nephrogenic diabetes insipidus: wild-type aquaporin-2 rescues the apical membrane expression of intracellularly retained AQP2-P262L.
abstract: Vasopressin regulates water homeostasis through insertion of homotetrameric aquaporin-2 (AQP2) water channels in the apical plasma membrane of renal cells. AQP2 mutations cause recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. Until now, all AQP2 mutants in recessive NDI were shown to be misfolded, retained in the endoplasmic reticulum (ER) and unable to interact with wild-type (wt)-AQP2, whereas AQP2 mutants in dominant NDI are properly folded and interact with wt-AQP2, but, due to the mutation, cause missorting of the wt-AQP2/mutant complex. Here, patients of two families with recessive NDI appeared compound heterozygotes for AQP2-A190T or AQP2-R187C mutants, together with AQP2-P262L. As mutations in the AQP2 C-tail, where P262 resides, usually cause dominant NDI, the underlying cell-biological mechanism was investigated. Upon expression in oocytes, AQP2-P262L was a properly folded and functional aquaporin in contrast to the classical mutants, AQP2-R187C and AQP2-A190T. Expressed in polarized cells, AQP2-P262L was retained in intracellular vesicles and did not localize to the ER. Upon co-expression, however, AQP2-P262L interacted with wt-AQP2, but not with AQP2-R187C, resulting in a rescued apical membrane expression of AQP2-P262L. In conclusion, our study reveals a novel cellular phenotype in recessive NDI in that AQP2-P262L acts as a mutant in dominant NDI, except for that its missorting is overruled by apical sorting of wt-AQP2. Also, it demonstrates for the first time that the recessive inheritance of a disease involving a channel can be due to two cell-biological mechanisms.
authors.affiliation: Department of Physiology, Radboud University of Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: de Mattia
authors.forename: Paul J M
authors.initials: PJ
authors.lastname: Savelkoul
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.forename: Irene B M
authors.initials: IB
authors.lastname: Konings
authors.forename: Nannette
authors.initials: N
authors.lastname: Marr
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Arthus
authors.forename: Michèle
authors.initials: M
authors.lastname: Lonergan
authors.forename: Carel H
authors.initials: CH
authors.lastname: van Os
authors.forename: Peter
authors.initials: P
authors.lastname: van der Sluijs
authors.forename: Gary
authors.initials: G
authors.lastname: Robertson
authors.forename: Peter M T
authors.initials: PM
authors.lastname: Deen
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D051399:Aquaporin 2; D020346:Aquaporins / Q000235:genetics* / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017433:Protein Structure, Secondary; D014981:Xenopus
chemical_list: C496023:AQP2 protein, human; D051399:Aquaporin 2; D020346:Aquaporins