title: Type of uromodulin mutation and allelic status influence onset and severity of uromodulin-associated kidney disease in mice.
abstract: Uromodulin-associated kidney disease (UAKD) is a dominant heritable renal disease in humans which is caused by mutations in the uromodulin (UMOD) gene and characterized by heterogeneous clinical appearance. To get insights into possible causes of this heterogeneity of UAKD, we describe the new mutant mouse line Umod(C93F), leading to disruption of a putative disulfide bond which is also absent in a known human UMOD mutation, and compare the phenotype of this new mouse line with the recently published mouse line Umod(A227T). In both mutant mouse lines, which were both bred on the C3H background, the Umod mutations cause a gain-of-toxic function due to a maturation defect of the mutant uromodulin leading to a dysfunction of thick ascending limb of Henle's loop (TALH) cells of the kidney. Umod mutant mice exhibit increased plasma urea and Cystatin levels, impaired urinary concentration ability, reduced fractional excretion of uric acid and nephropathological alterations including uromodulin retention in TALH cells, interstitial fibrosis and inflammatory cell infiltrations, tubular atrophy and occasional glomerulo- und tubulocystic changes, a phenotype highly similar to UAKD in humans. The maturation defect of mutant uromodulin leads to the accumulation of immature uromodulin in the endoplasmic reticulum (ER) and to ER hyperplasia. Further, this study was able to demonstrate for the first time in vivo that the severity of the uromodulin maturation defect as well as onset and speed of progression of renal dysfunction and morphological alterations are strongly dependent on the particular Umod mutation itself and the zygosity status.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
authors.forename: Petra
authors.initials: P
authors.lastname: Prueckl
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sklenak
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Felix A
authors.initials: FA
authors.lastname: Habermann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Bernhard
authors.initials: B
authors.lastname: Aigner
authors.forename: Ruediger
authors.initials: R
authors.lastname: Wanke
mesh_terms: D017668:Age of Onset; D000483:Alleles; D000818:Animals; D001835:Body Weight; D015891:Cystatins / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D006073:Gout / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice / Q000235:genetics* / Q000254:growth & development; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D010641:Phenotype; D017354:Point Mutation; D014508:Urea / Q000097:blood; D014527:Uric Acid / Q000652:urine; D058949:Uromodulin / Q000235:genetics* / Q000652:urine
chemical_list: D015891:Cystatins; D058949:Uromodulin; D014527:Uric Acid; D014508:Urea