Journal Article

Disease mechanisms in late-onset retinal macular degeneration associated with mutation in <i>C1QTNF5</i>

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

in Human Molecular Genetics

Volume 15, issue 10, pages 1680-1689
Published in print May 2006 | ISSN: 0964-6906
Published online April 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl091
Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5

Show Summary Details

Preview

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.

Journal Article.  7042 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.