Pathogenic uromodulin mutations result in premature intracellular polymerization

• Published in: FEBS letters Vol. 589; no. 1; pp. 89 - 93
• Main Authors: Stewart, Andrew P., Sandford, Richard N., Karet Frankl, Fiona E., Edwardson, J. Michael
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 02.01.2015
• Subjects: AFM; Amino Acid Substitution; Atomic force microscopy; chronic kidney disease; CKD; electron microscopy; Familial Juvenile Hyperuricemic Nephropathy; Female; FJHN; Genetic Diseases, Inborn - genetics; Genetic Diseases, Inborn - pathology; Genetic Diseases, Inborn - urine; HEK293 Cells; hemagglutinin; Humans; Kidney Diseases - genetics; Kidney Diseases - pathology; Kidney Diseases - urine; Male; MCKD; Medullary Cystic Kidney Disease; Mutation, Missense; Nephropathy; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - pathology; Protein Aggregation, Pathological - urine; Protein polymerization; Protein Transport - genetics; SDS–PAGE; SDS–polyacrylamide gel electrophoresis; Uromodulin; Uromodulin - genetics; Uromodulin - urine; Atomic force microscopy; Nephropathy; Protein polymerization; AFM; EM; HA; FJHN; MCKD; Uromodulin; SDS–PAGE; CKD
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2014.11.029

•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.