title: Urinary secretion and extracellular aggregation of mutant uromodulin isoforms.
abstract: Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra- and extracellular forms of the protein.
authors.affiliation: Dulbecco Telethon Institute, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Céline
authors.initials: C
authors.lastname: Schaeffer
authors.forename: Angela
authors.initials: A
authors.lastname: Cattaneo
authors.forename: Matteo
authors.initials: M
authors.lastname: Trudu
authors.forename: Sara
authors.initials: S
authors.lastname: Santambrogio
authors.forename: Ilenia
authors.initials: I
authors.lastname: Bernascone
authors.forename: Daniela
authors.initials: D
authors.lastname: Giachino
authors.forename: Gianluca
authors.initials: G
authors.lastname: Caridi
authors.forename: Andrea
authors.initials: A
authors.lastname: Campo
authors.forename: Corrado
authors.initials: C
authors.lastname: Murtas
authors.forename: Simona
authors.initials: S
authors.lastname: Benoni
authors.forename: Claudia
authors.initials: C
authors.lastname: Izzi
authors.forename: Mario
authors.initials: M
authors.lastname: De Marchi
authors.forename: Antonio
authors.initials: A
authors.lastname: Amoroso
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
authors.forename: Francesco
authors.initials: F
authors.lastname: Scolari
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.forename: Luca
authors.initials: L
authors.lastname: Rampoldi
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics / Q000652:urine; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000652:urine*; D010375:Pedigree; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000652:urine; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058949:Uromodulin / Q000737:chemistry* / Q000235:genetics / Q000652:urine*
chemical_list: D050505:Mutant Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins; C548612:UMOD protein, human; D058949:Uromodulin