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

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

Research output: Contribution to journalArticle

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)1680-1689
JournalHuman Molecular Genetics
Volume15
Issue number10
DOIs
Publication statusPublished - 6 Apr 2006

Fingerprint

Macular Degeneration
Retinal Pigments
Endoplasmic Reticulum
Mutation
Mutant Proteins
Non-Fibrillar Collagens
Collagen Diseases
Proteasome Endopeptidase Complex
Immunoprecipitation
Half-Life
Yeasts
Epithelial Cells
Membranes
Late-Onset Retinal Degeneration
Genes
Proteins

Keywords

  • immunoprecipitation
  • yeast one/two-hybrid system
  • mutation
  • collagen
  • genetics
  • tissue membrane
  • yeasts
  • macular degeneration
  • mice
  • mutant proteins
  • retinal pigment cell

Cite this

Shu, Xinhua ; Lennon, Alan ; Vlachantoni, Dafni ; Zhou, Xinzhi ; Hayward, Caroline ; Wright, Alan F. . / Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5. In: Human Molecular Genetics. 2006 ; Vol. 15, No. 10. pp. 1680-1689.
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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.",
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Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5. / Shu, Xinhua; Lennon, Alan; Vlachantoni, Dafni; Zhou, Xinzhi; Hayward, Caroline; Wright, Alan F. .

In: Human Molecular Genetics, Vol. 15, No. 10, 06.04.2006, p. 1680-1689.

Research output: Contribution to journalArticle

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T1 - Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5

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AU - Lennon, Alan

AU - Vlachantoni, Dafni

AU - Zhou, Xinzhi

AU - Hayward, Caroline

AU - Wright, Alan F.

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