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 journal › Article

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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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.",
keywords = "immunoprecipitation, yeast one/two-hybrid system, mutation, collagen, genetics, tissue membrane, yeasts, macular degeneration, mice, mutant proteins, retinal pigment cell",
author = "Xinhua Shu and Alan Lennon and Dafni Vlachantoni and Xinzhi Zhou and Caroline Hayward and Wright, {Alan F.}",
year = "2006",
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Shu, X, Lennon, A, Vlachantoni, D, Zhou, X, Hayward, C & Wright, AF 2006, 'Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5', Human Molecular Genetics, vol. 15, no. 10, pp. 1680-1689. https://doi.org/10.1093/hmg/ddl091

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 journal › Article

TY - JOUR

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

AU - Shu, Xinhua

AU - Lennon, Alan

AU - Vlachantoni, Dafni

AU - Zhou, Xinzhi

AU - Hayward, Caroline

AU - Wright, Alan F.

PY - 2006/4/6

Y1 - 2006/4/6

N2 - 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.

AB - 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.

KW - immunoprecipitation

KW - yeast one/two-hybrid system

KW - mutation

KW - collagen

KW - genetics

KW - tissue membrane

KW - yeasts

KW - macular degeneration

KW - mice

KW - mutant proteins

KW - retinal pigment cell

U2 - 10.1093/hmg/ddl091

DO - 10.1093/hmg/ddl091

M3 - Article

VL - 15

SP - 1680

EP - 1689

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 10

ER -

Shu X, Lennon A, Vlachantoni D, Zhou X, Hayward C, Wright AF. Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5. Human Molecular Genetics. 2006 Apr 6;15(10):1680-1689. https://doi.org/10.1093/hmg/ddl091

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