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Human Molecular Genetics Advance Access published online on April 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl091
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received January 31, 2006
Revised March 29, 2006
Accepted March 29, 2006

Article

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

Xinhua Shu 1 *, Brian Tulloch 1, Alan Lennon 1, Dafni Vlachantoni 1, Xinzhi Zhou 1, Caroline Hayward 1, and Alan F. Wright 1

1 MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.

* To whom correspondence should be addressed.
Xinhua Shu, E-mail: xinhua.shu{at}hgu.mrc.ac.uk


  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 show firstly that wildtype 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 wildtype 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-localisation. 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.


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