Mutations in the chloride-proton antiporter, ClC-5, cause Dent’s disease, a kidney disease defined by excessive loss of proteins in the urine. ClC-5 resides on early endosomal membranes in proximal tubule epithelial cells, where it facilitates protein receptor-mediated endocytosis. Loss-of-function mutations in ClC-5 produce proximal tubule defects in protein reabsorption. This study characterized an epithelial cell phenotype for nonsense ClC-5 mutations, R648X and R704X. Both ClC-5 mutants displayed defective biosynthesis, mistrafficking and ER
localization. This study showed that ClC-5 mutations, R718X and C221R, which are also misprocessed and ER retained, are targeted for proteasomal degradation as a means to be efficiently eliminated from the ER. In addition, we have shown that a missense mutation in ClC-
5, C221R, causes a global conformational change in the antiporter, which likely reflects protein
misfolding, as evident by enhanced susceptibility to trypsin proteolysis. We have characterized ClC-5 disease-causing mutations in an epithelial cell model of the proximal tubule.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/35515 |
| Date | 27 June 2013 |
| Creators | D'Antonio, Christina |
| Contributors | Bear, Christine |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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