title: A new missense mutation in UMOD gene leads to severely reduced serum uromodulin concentrations - A tool for the diagnosis of uromodulin-associated kidney disease.
abstract: BACKGROUND
  Uromodulin-associated Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD-UMOD) belongs to a group of autosomal dominant inherited diseases caused by mutations in the UMOD gene, which codes for uromodulin, a protein exclusively expressed in renal tubular cells of the ascending limb of the loop of Henle. The diagnosis is hampered by non-specific clinical, laboratory and histological findings. In this study, we evaluated serum uromodulin as diagnostic marker for ADTKD-UMOD in a family with a novel mutation in UMOD.
  
  
  METHODS
  We investigated a family with five members suffering from chronic kidney disease of unknown origin (CKD) and three healthy members using whole exome sequencing. Serum uromodulin was measured by ELISA. The uromodulin concentration of each CKD family member was compared to reference CKD groups with similar eGFR and to non-CKD individuals in case of the healthy family members, respectively.
  
  
  RESULTS
  Whole exome sequencing revealed novel missense mutation c.457T>G, p.(Cys153Gly) in UMOD. Serum uromodulin concentration was lower in all affected patients compared to all patients of the reference CKD groups, while healthy family members showed normal values comparable to those of the non-CKD reference group.
  
  
  CONCLUSIONS
  The mutation detected in our family leads to severely reduced serum uromodulin concentrations, distinguishing these patients clearly from CKD patients with comparable eGFR. Therefore, serum uromodulin could serve as a simple, new diagnostic marker to identify patients with ADTKD-UMOD.
authors.affiliation: Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, München, Germany; Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Satanovskij
authors.affiliation: Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, München, Germany; Institut für Humangenetik, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Alhaddad
authors.initials: A
authors.lastname: Bader
authors.affiliation: Euroimmun Medizinische Labordiagnostika AG, Lübeck, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Block
authors.affiliation: Euroimmun Medizinische Labordiagnostika AG, Lübeck, Germany.
authors.forename: Victor
authors.initials: V
authors.lastname: Herbst
authors.affiliation: Euroimmun Medizinische Labordiagnostika AG, Lübeck, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schlumberger
authors.affiliation: Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, München, Germany; Institut für Humangenetik, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Haack
authors.affiliation: Institut für Institut für Laboratoriumsmedizin und Pathobiochemie, Molekulare Diagnostik, Universitätsklinikum Marburg, Philipps-Universität Marburg, Marburg, Germany.
authors.forename: Wolfgang Andreas
authors.initials: WA
authors.lastname: Nockher
authors.affiliation: Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Heemann
authors.affiliation: Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Renders
authors.affiliation: Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmaderer
authors.affiliation: Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Angermann
authors.affiliation: Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Ming
authors.initials: M
authors.lastname: Wen
authors.affiliation: Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, München, Germany; Institut für Humangenetik, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Klinikum München-Harlaching, Teaching-hospital of the Ludwig-Maximilians-Universität München, München, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scherberich
authors.affiliation: Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, München, Germany. Electronic address: dominik.steubl@lrz.tum.de.
authors.forename: Dominik
authors.initials: D
authors.lastname: Steubl
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D058949:Uromodulin / Q000235:genetics*
chemical_list: D058949:Uromodulin; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: ADTKD-UMOD; Biomarker; Chronic kidney disease; FJHN; Proteinuria; Tamm-Horsfall protein; Tubulointerstitial disease; UAKD; Uromodulin; eGFR