Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5

Xinhua Shu, Brian Tulloch, Alan Lennon, Dafni Vlachantoni, Xinzhi Zhou, Caroline Hayward, Alan F Wright

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)1680-9
Number of pages10
JournalHuman Molecular Genetics
Volume15
Issue number10
DOIs
Publication statusPublished - 2006

Fingerprint

Dive into the research topics of 'Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5'. Together they form a unique fingerprint.

Cite this