Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5
Open Access
- 6 April 2006
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 15 (10), 1680-1689
- https://doi.org/10.1093/hmg/ddl091
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.This publication has 31 references indexed in Scilit:
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