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Pathogenic uromodulin mutations result in premature intracellular polymerization
Author(s) -
Stewart Andrew P.,
Sandford Richard N.,
Karet Frankl Fiona E.,
Edwardson J. Michael
Publication year - 2015
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.11.029
Subject(s) - tamm–horsfall protein , intracellular , mutant , transfection , mutation , microbiology and biotechnology , biology , chemistry , gene , biochemistry , genetics , kidney
Several renal diseases involve mutations in the gene encoding uromodulin, the predominant protein in urine. We investigated the intracellular processing of wild‐type uromodulin, and three mutants: p.V93_G97del/ins AASC; C155R; and C150S. A renal biopsy from a patient harboring the C155R mutation revealed intracellular protein accumulation. Wild‐type uromodulin was efficiently trafficked to the cell surface in transfected tsA 201 cells, whereas the mutants were partially retained within the cell, and incompletely processed. Atomic force microscopy imaging revealed that the intracellular mutant proteins contained fibrillar structures similar to urinary uromodulin. We suggest that premature intracellular polymerization underlies the pathology of uromodulin diseases.