title: Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression.
abstract: Uromodulin (UMOD) mutations are responsible for three autosomal dominant tubulo-interstitial nephropathies including medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Symptoms include renal salt wasting, hyperuricemia, gout, hypertension and end-stage renal disease. MCKD is part of the 'nephronophthisis-MCKD complex', a group of cystic kidney diseases. Both disorders have an indistinguishable histology and renal cysts are observed in either. For most genes mutated in cystic kidney disease, their proteins are expressed in the primary cilia/basal body complex. We identified seven novel UMOD mutations and were interested if UMOD protein was expressed in the primary renal cilia of human renal biopsies and if mutant UMOD would show a different expression pattern compared with that seen in control individuals. We demonstrate that UMOD is expressed in the primary cilia of renal tubules, using immunofluorescent studies in human kidney biopsy samples. The number of UMOD-positive primary cilia in UMOD patients is significantly decreased when compared with control samples. Additional immunofluorescence studies confirm ciliary expression of UMOD in cell culture. Ciliary expression of UMOD is also confirmed by electron microscopy. UMOD localization at the mitotic spindle poles and colocalization with other ciliary proteins such as nephrocystin-1 and kinesin family member 3A is demonstrated. Our data add UMOD to the group of proteins expressed in primary cilia, where mutations of the gene lead to cystic kidney disease.
authors.affiliation: Center for Biochemistry, Medical Faculty, University Children's Hospital, University of Cologne, Cologne, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Zaucke
authors.forename: Joana M
authors.initials: JM
authors.lastname: Boehnlein
authors.forename: Sarah
authors.initials: S
authors.lastname: Steffens
authors.forename: Roman S
authors.initials: RS
authors.lastname: Polishchuk
authors.forename: Luca
authors.initials: L
authors.lastname: Rampoldi
authors.forename: Andreas
authors.initials: A
authors.lastname: Fischer
authors.forename: Andreas
authors.initials: A
authors.lastname: Pasch
authors.forename: Christoph W A
authors.initials: CW
authors.lastname: Boehm
authors.forename: Anne
authors.initials: A
authors.lastname: Baasner
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
authors.forename: Bernd
authors.initials: B
authors.lastname: Hoppe
authors.forename: Helmut
authors.initials: H
authors.lastname: Hopfer
authors.forename: Bodo B
authors.initials: BB
authors.lastname: Beck
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Matthias T F
authors.initials: MT
authors.lastname: Wolf
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001706:Biopsy; D015153:Blotting, Western; D002455:Cell Division; D002478:Cells, Cultured; D002648:Child; D002923:Cilia / Q000378:metabolism* / Q000648:ultrastructure; D003598:Cytoskeletal Proteins; D005455:Fluorescent Antibody Technique; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D016547:Kinesins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009088:Mucoproteins / Q000276:immunology / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D014162:Transfection; D058949:Uromodulin; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D003598:Cytoskeletal Proteins; C490202:Kif3a protein, mouse; D008565:Membrane Proteins; D009088:Mucoproteins; D050505:Mutant Proteins; C108725:NPHP1 protein, human; C548612:UMOD protein, human; C548613:Umod protein, mouse; D058949:Uromodulin; D016547:Kinesins