Pathogenic uromodulin mutations result in premature intracellular polymerization

•Several renal diseases involve mutations in uromodulin, the major protein in urine.•A renal biopsy from a patient showed intracellular accumulation of mutant uromodulin.•Mutants were partially retained within transfected cells, and incompletely processed.•Intracellular mutants contained fibrillar structures, similar to urinary uromodulin.•Intracellular polymerization may underlie the pathology of uromodulin diseases.

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.