Abstract
Late-onset retinal macular degeneration (L-ORMD) is an autosomal dominant condition resembling age-related macular degeneration (AMD) in which a key pathological feature is a thick extracellular sub-retinal pigment epithelial (RPE) deposit. L-ORMD is caused by mutation in the C1QTNF5 ( CTRP5 ) short-chain collagen gene, but the disease mechanism is unknown. Here, we first show that wild-type C1QTNF5 is secreted, whereas mutant C1QTNF5 is misfolded and retained within the endoplasmic reticulum (ER). Secondly, the ER retained mutant protein has a shorter half-life than wild-type C1QTNF5 and is preferentially degraded by proteasomes. Thirdly, C1QTNF5 is shown to interact with the membrane-type frizzled related protein (MFRP), on the basis of yeast two-hybrid, protein pull-down and co-immunoprecipitation assays and RPE co-localization. These data suggest that L-ORMD is due to insufficient levels of secreted C1QTNF5, compromised RPE cell function resulting from ER retention of the mutant protein or both mechanisms.
Original language | English |
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Pages (from-to) | 1680-1689 |
Journal | Human Molecular Genetics |
Volume | 15 |
Issue number | 10 |
DOIs | |
Publication status | Published - 6 Apr 2006 |
Keywords
- immunoprecipitation
- yeast one/two-hybrid system
- mutation
- collagen
- genetics
- tissue membrane
- yeasts
- macular degeneration
- mice
- mutant proteins
- retinal pigment cell