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Astra Dinculescu, Seok-Hong Min, Frank M Dyka, Renee C Ryals, Vince Chiodo, William W Hauswirth; Over-expression of human mutant C1QTNF5 (Ser163Arg) in RPE cells leads to both RPE and photoreceptor cell loss in wild-type mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2188.
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© ARVO (1962-2015); The Authors (2016-present)
The pathogenic mutation S163R in the gC1q domain of the complement C1q tumor necrosis factor-related protein-5 (C1QTNF5/CTRP5) causes autosomal dominant late-onset retinal degeneration (L-ORD) in humans. Here, our goal was to test the effects of mutant S163R C1QTNF5 protein overexpression in RPE cells following AAV-mediated delivery to wild-type mouse eyes.
We generated scAAV vectors (AAV2 or AAV8Y733F) containing either human wild-type C1QTNF5 or mutant S163R C1QTNF5, driven by an RPE-specific BEST1 promoter, and delivered them subretinally into one eye of adult C57BL/6 mice, while the contralateral eyes remained untreated and served as controls. Retinal function was assessed by full-field electroretinography (ERG) under scotopic (dark-adapted) and photopic conditions at 1 month post-injection. Digital fundus imaging, evaluation of retinal morphology by hematoxylin and eosin staining of paraffin sections, and immunohistochemistry were also performed.
RPE targeted overexpression of S163R C1QTNF5 mutant leads to widespread photoreceptor degeneration, thinning and loss of RPE cells. In contrast, abnormally high levels of wild-type C1QTNF5 causes dramatically enlarged RPE cells, loss of RPE intercellular integrity and depigmentation, consistent with our previous findings. Treatment with either wild-type or mutant C1QTNF5 leads to significantly reduced a- and b-wave ERG amplitudes when examined at 1 month post-injection, and loss of cells from both the outer and inner retina. Interestingly, treated retinas retain an organized laminar structure, as they become rapidly thinner in only 4 months post-injection.
Overexpression of the S163R mutant C1QTNF5 in the RPE of normal mice exerts pathological effects similar to some of those found in patients with autosomal dominant late-onset retinal degeneration, such as RPE thinning, RPE cell loss, and retinal degeneration. These results support the hypothesis that L-ORD caused by the S163R mutation may result from a toxic gain of function of the mutant C1QTNF5 protein. Results of wild-type C1QTNF5 overexpression suggest that simple gene augmentation of L-ORD with wild-type C1QTNF5 may not be therapeutic.
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