The Characterization of Retinal Phenotype in a Family With C1qtnf5-Related Late-Onset Retinal Degeneration

Vincent, Ajoy; Munier, Francis L.; VandenHoven, Cynthia; Wright, Tom; Westall, Carol A.; Hèon, Elise

doi:10.1097/iae.0b013e318240a574

Cited by 33 publications

(111 citation statements)

References 20 publications

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“…The reticular lesions in this present study could be described as drusen-like based on color fundus photos, but OCT demonstrates their subretinal location. Two recent publications 8, 9 have described FAF and OCT findings in L-ORD that could represent components of the disease progression observed in our patients. Vincent et al described flecks of hyper- and hypoautofluorescence adjacent to the region of atrophy 8 , which may be the same as the mottled autofluorescence in our patient 2.…”

Section: Discussionsupporting

confidence: 51%

“…Two recent publications 8, 9 have described FAF and OCT findings in L-ORD that could represent components of the disease progression observed in our patients. Vincent et al described flecks of hyper- and hypoautofluorescence adjacent to the region of atrophy 8 , which may be the same as the mottled autofluorescence in our patient 2. They also mentioned “nodes of thickening of the RPE” over areas of RPE/Bruch’s membrane separation 8 , which is similar to findings we observed in this study, with separation of the RPE and Bruch’s membrane following thickening of the RPE.…”

Section: Discussionsupporting

confidence: 51%

“…As the disease progresses, scalloped chorioretinal atrophy develops in the temporal retina, which then spreads towards the fovea 6, 7 . Visual acuity is usually preserved until at least the seventh decade when the fovea is compromised by either progressive atrophy or the development of choroidal neovascularization 3, 6, 8 .…”

mentioning

confidence: 99%

“…Fundus autofluorescence findings include scalloped hypoautofluorescent patches corresponding to areas of chorioretinal atrophy with adjacent areas of speckled hyper- and hypo-autofluorescence 8, 9 . SD-OCT showed sub-RPE deposits with marked disturbances of the photoreceptor outer segments, ellipsoid zone (EZ), and outer nuclear layer (ONL) overlying these areas 9 .…”

mentioning

confidence: 99%

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Longitudinal Structural Changes in Late-Onset Retinal Degeneration

Cukras

Flamendorf

Wong

et al. 2016

Retina

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Purpose To characterize longitudinal structural changes in early stages of late-onset retinal degeneration (L-ORD) to investigate pathogenic mechanisms. Methods Two affected siblings, both with a S163R missense mutation in the causative gene C1QTNF5, were followed for 8+ years. Color fundus photos, fundus autofluorescence (FAF) images, near infrared reflectance (NIR-R) fundus images, and spectral domain optical coherence tomography (SD-OCT) scans were acquired during follow-up. Results Both patients, aged 45 and 50 years, had good visual acuities (> 20/20 OU) in the context of prolonged dark adaptation. Baseline color fundus photography demonstrated yellow-white, punctate lesions in the temporal macula that correlated with a reticular pattern on FAF and NIR-R imaging. Baseline SD-OCT imaging revealed subretinal deposits that resemble reticular pseudodrusen (RPD) described in age-related macular degeneration (AMD). During follow-up, these affected areas developed confluent thickening of the retinal pigment epithelial (RPE) layer and disruption of the ellipsoid zone of photoreceptors before progressing to overt RPE and outer retinal atrophy. Conclusions Structural changes in early stage L-ORD revealed by multimodal imaging resemble those of RPD observed in AMD and other retinal diseases. Longitudinal follow-up of these lesions helps elucidate their progression to frank atrophy and may lend insight into the pathogenic mechanisms underlying diverse retinal degenerations.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionsupporting

confidence: 51%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Longitudinal Structural Changes in Late-Onset Retinal Degeneration

Cukras

Flamendorf

Wong

et al. 2016

Retina

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“…Reports have illustrated focal sub-RPE material associated with drusen-like lesions in L-ORD. 4,5 We studied members of the original family with L-ORD, proven to have the p.Ser163Arg mutation in C1QTNF5, and asked whether retina-wide sub-RPE deposit was detectable and quantifiable. The relationship of deposit to photoreceptor structure and co-localized rod and cone vision was determined.…”

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confidence: 99%

Late-Onset Retinal Degeneration Caused byC1QTNF5Mutation

et al. 2014

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Extracellular vesicles from retinal pigment epithelial cells expressing R345W‐Fibulin‐3 induce epithelial‐mesenchymal transition in recipient cells

Zhou,

Zhao,

Weber

et al. 2023

J of Extracellular Vesicle

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We have shown previously that expression of R345W‐Fibulin‐3 induces epithelial‐mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells. The purpose of the current study was to determine if extracellular vesicles (EVs) derived from RPE cells expressing R345W‐Fibulin‐3 mutation are sufficient to induce EMT in recipient cells. ARPE‐19 cells were infected with luciferase‐tagged wild‐type (WT)‐ Fibulin‐3 or luciferase‐tagged R345W‐Fibulin‐3 (R345W) using lentiviruses. EVs were isolated from the media by ultracentrifugation or density gradient ultracentrifugation. Transmission electron microscopy and cryogenic electron microscopy were performed to study the morphology of the EVs. The size distribution of EVs were determined by nanoparticle tracking analysis (NTA). EV cargo was analysed using LC‐MS/MS based proteomics. EV‐associated transforming growth factor beta 1 (TGFβ1) protein was measured by enzyme‐linked immunosorbent assay. The capacity of EVs to stimulate RPE migration was evaluated by treating recipient cells with WT‐ or R345W‐EVs. The role of EV‐bound TGFβ was determined by pre‐incubation of EVs with a pan‐TGFβ blocking antibody or IgG control. EM imaging revealed spherical vesicles with two subpopulations of EVs: a group with diameters around 30 nm and a group with diameters over 100 nm, confirmed by NTA analysis. Pathway analysis revealed that members of the sonic hedgehog pathway were less abundant in R345W‐ EVs, while EMT drivers were enriched. Additionally, R345W‐EVs had higher concentrations of TGFβ1 compared to control. Critically, treatment with R345W‐EVs was sufficient to increase EMT marker expression, as well as cell migration in recipient cells. This EV‐increased cell migration was significantly inhibited by pre‐incubation of EVs with pan‐TGFβ‐neutralising antibody. In conclusion, the expression of R345W‐Fibulin‐3 alters the size and cargo of EVs, which are sufficient to enhance the rate of cell migration in a TGFβ dependent manner. These results suggest that EV‐bound TGFβ plays a critical role in the induction of EMT in RPE cells.

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The Characterization of Retinal Phenotype in a Family With C1qtnf5-Related Late-Onset Retinal Degeneration

Cited by 33 publications

References 20 publications

Longitudinal Structural Changes in Late-Onset Retinal Degeneration

Longitudinal Structural Changes in Late-Onset Retinal Degeneration

Late-Onset Retinal Degeneration Caused byC1QTNF5Mutation

Extracellular vesicles from retinal pigment epithelial cells expressing R345W‐Fibulin‐3 induce epithelial‐mesenchymal transition in recipient cells

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