Pathogenic uromodulin mutations result in premature intracellular polymerization.

Andrew P Stewart, Richard N Sandford, Fiona E Karet Frankl, J Michael Edwardson

Journal: FEBS letters 2015;589(1):89-93

PMID: 25436415

Abstract

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.

Address: Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Electronic address: [email protected].; Department of Medical Genetics, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.; Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.

DOI: 10.1016/j.febslet.2014.11.029

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MeSH Terms: Amino Acid Substitution, Female, Genetic Diseases, Inborn, HEK293 Cells, Humans, Kidney Diseases, Male, Mutation, Missense, Protein Aggregation, Pathological, Protein Transport, Uromodulin