Stanton, Chloe M, Borooah, Shyamanga, Drake, Camilla, Marsh, Joseph A, Campbell, Susan, Lennon, Alan, Soares, Dinesh C, Vallabh, Neeru A 
ORCID: 0000-0002-0109-4112, Sahni, Jayashree, Cideciyan, Artur V et al (show 5 more authors)
(2017)
Novel pathogenic mutations in <i>C1QTNF5</i> support a dominant negative disease mechanism in late-onset retinal degeneration.
SCIENTIFIC REPORTS, 7 (1).
12147-.
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Novel pathogenic mutations in C1QTNF5 support a dominant negative disease mechanism in late-onset retinal degeneration.pdf - Published version Download (3MB) | Preview |
Abstract
Late-onset retinal degeneration (L-ORD) is a rare autosomal dominant retinal dystrophy, characterised by extensive sub-retinal pigment epithelium (RPE) deposits, RPE atrophy, choroidal neovascularisation and photoreceptor cell death associated with severe visual loss. L-ORD shows striking phenotypic similarities to age-related macular degeneration (AMD), a common and genetically complex disorder, which can lead to misdiagnosis in the early stages. To date, a single missense mutation (S163R) in the C1QTNF5 gene, encoding C1q And Tumor Necrosis Factor Related Protein 5 (C1QTNF5) has been shown to cause L-ORD in a subset of affected families. Here, we describe the identification and characterisation of three novel pathogenic mutations in C1QTNF5 in order to elucidate disease mechanisms. In silico and in vitro characterisation show that these mutations perturb protein folding, assembly or polarity of secretion of C1QTNF5 and, importantly, all appear to destabilise the wildtype protein in co-transfection experiments in a human RPE cell line. This suggests that the heterozygous mutations in L-ORD show a dominant negative, rather than a haploinsufficient, disease mechanism. The function of C1QTNF5 remains unclear but this new insight into the pathogenetic basis of L-ORD has implications for future therapeutic strategies such as gene augmentation therapy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Cell Line, Humans, Retinal Degeneration, Collagen, Pedigree, Sequence Alignment, Amino Acid Sequence, Protein Folding, Mutation, Mutation, Missense, Models, Molecular, Aged, Middle Aged, Female, Male, Protein Domains |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 16 May 2019 09:23 |
| Last Modified: | 11 Oct 2023 16:56 |
| DOI: | 10.1038/s41598-017-11898-3 |
| Open Access URL: | http://doi.org/10.1038/s41598-017-11898-3 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3041586 |
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