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Hum Mol Genet. 2006 May 15;15(10):1680-9. Epub 2006 Apr 6.

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

Author information

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

PMID:
16600989
DOI:
10.1093/hmg/ddl091
[Indexed for MEDLINE]

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