title: Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5.
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.
authors.affiliation: MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK. xinhua.shu@hgu.mrc.ac.uk
authors.forename: Xinhua
authors.initials: X
authors.lastname: Shu
authors.forename: Brian
authors.initials: B
authors.lastname: Tulloch
authors.forename: Alan
authors.initials: A
authors.lastname: Lennon
authors.forename: Dafni
authors.initials: D
authors.lastname: Vlachantoni
authors.forename: Xinzhi
authors.initials: X
authors.lastname: Zhou
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
mesh_terms: D017668:Age of Onset; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D003094:Collagen / Q000235:genetics / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010857:Pigment Epithelium of Eye / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D011485:Protein Binding; D017510:Protein Folding; D000099274:Frizzled-Related Proteins
chemical_list: D003094:Collagen; D005136:Eye Proteins; D008565:Membrane Proteins; D046988:Proteasome Endopeptidase Complex; C487851:C1QTNF5 protein, human; C423368:Mfrp protein, mouse; D000099274:Frizzled-Related Proteins