HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/F1391    most recent 00261.2009v2 00261.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kemter, E. Articles by Aigner, B. PubMed PubMed Citation Articles by Kemter, E. Articles by Aigner, B.

Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism

¹Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis, Gene Center, and ; ⁵Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität Munich, Munich; ; ²Molecular Nutricial Medicine, Else-Kröner-Fresenius Center, Technische Universität München, Freising-Weihenstephan; ; ³Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, and Chair for Experimental Genetics, Technische Universität München, Munich; and ; ⁴Department of Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany

Submitted May 10, 2009 ; accepted in final form August 14, 2009

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.

N-ethyl-N-nitrosourea; kidney; renal disease; Umod