title: Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism.
abstract: Uromodulin-associated kidney disease is a heritable renal disease in humans caused by mutations in the uromodulin (UMOD) gene. The pathogenesis of the disease is mostly unknown. In this study, we describe a novel chemically induced mutant mouse line termed Umod(A227T) exhibiting impaired renal function. The A227T amino acid exchange may impair uromodulin trafficking, leading to dysfunction of thick ascending limb cells of Henle's loop of the kidney. As a consequence, homozygous mutant mice display azotemia, impaired urine concentration ability, reduced fractional excretion of uric acid, and a selective defect in concentrating urea. Osteopenia in mutant mice is presumably a result of chronic hypercalciuria. In addition, body composition, lipid, and energy metabolism are indirectly affected in heterozygous and homozygous mutant Umod(A227T) mice, manifesting in reduced body weight, fat mass, and metabolic rate as well as reduced blood cholesterol, triglycerides, and nonesterified fatty acids. In conclusion, Umod(A227T) might act as a gain-of-toxic-function mutation. Therefore, the Umod(A227T) mouse line provides novel insights into consequences of disturbed uromodulin excretion regarding renal dysfunction as well as bone, energy, and lipid metabolism.
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität Munich, Munich, Germany. kemter@lmb.uni-muenchen.de
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Anja
authors.initials: A
authors.lastname: Schrewe
authors.forename: Christina
authors.initials: C
authors.lastname: Landbrecht
authors.forename: Matthias
authors.initials: M
authors.lastname: Klaften
authors.forename: Boris
authors.initials: B
authors.lastname: Ivandic
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Ruediger
authors.initials: R
authors.lastname: Wanke
authors.forename: Bernhard
authors.initials: B
authors.lastname: Aigner
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D001842:Bone and Bones / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D006339:Heart Rate / Q000502:physiology; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009088:Mucoproteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D013045:Species Specificity; D014508:Urea / Q000378:metabolism* / Q000652:urine; D058949:Uromodulin
chemical_list: D009088:Mucoproteins; C548612:UMOD protein, human; C548613:Umod protein, mouse; D058949:Uromodulin; D014508:Urea