A New CRB1 Rat Mutation Links Müller Glial Cells to Retinal Telangiectasia

Zhao, Min; Andrieu-Soler, Charlotte; Kowalczuk, Laura; Cortés, María Paz; Berdugo, Marianne; Dernigoghossian, Marilyn; Halili, Francisco; Jeanny, Jean‐Claude; Goldenberg, Brigitte; Savoldelli, Michéle; Sanharawi, Mohamed El; Naud, Marie‐Christine; IJcken, Wilfred F. J. van; Gobert, Rosanna Pescini; Martinet, Danielle; Maass, Alejandro; Wijnholds, Jan; Crisanti, Patricia; Rivolta, Carlo; Behar‐Cohen, Francine

doi:10.1523/jneurosci.3412-14.2015

Cited by 55 publications

(57 citation statements)

References 47 publications

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“…A rat model for MacTel carrying an insertiondeletion mutation within the gene Crb1 has been described 70 , however we find no associated signal at this locus either.…”

Section: Discussioncontrasting

confidence: 70%

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

et al. 2017

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Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genomewide association study (GWAS) with 476 cases and 1733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10 -8 ) were identified at 3 independent loci (rs73171800 at 5q14.3, P = 7.74 × 10 -17 ; rs715 at 2q34, P = 9.97 × 10 -14 ; rs477992 at 1p12, P = 2.60 × 10 -12 ) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences of blood serum levels of glycine (P = 4.04 × 10 -6 ) and serine (P = 2.48 × 10 -4 ) between MacTel cases and controls.MacTel cases typically present at 40-60 years with abnormal right-angled juxtafoveolar capillaries and parafoveal telangiectasias. It is an uncommon disease with a 0.0045-0.1% population prevalence and no obvious sex bias [1][2][3] . Retinal lesions typically co-present with MacTel, including retinal transparency, outer retinal and choroidal neovascularization, lamellar holes or foveal cysts, photoreceptor dysfunction, minimal exudation, yellow-white parafoveal crystals, and retinal pigment epithelial (RPE) pigmentation abnormalities and atrophy. Central vision impairment and decreased visual acuity are the usual clinical outcomes. MacTel is a bilateral disease, but asymmetry of the eyes for disease severity and presence of lesions is possible. The lesions also occur in 0.06-1.18% of the general population 2 .Risk factors for MacTel are largely unknown, however associations have been observed with smoking 2,4 , diabetes 5,6 , high BMI 6 , hypertension 6 and obesity 6 .Observations of MacTel affected monozygotic twins 4,[7][8][9] , and multiplex families with vertical transmissions of MacTel 1,5,[9][10][11][12] , suggest a genetic etiology for the disease. The late-age of onset, low penetrance and variable phenotype as exemplified by asymptomatic affected relatives 9 , and positive and negative misdiagnoses, complicate the discovery of genetic variants predisposing to MacTel. We previously screened 27 candidate genes in 8 unrelated MacTel cases but found no causative mutations 13 . Linkage analysis of 17 families with MacTel individuals identified a 15.3Mb locus on chromosome 1q41-42.2 (LOD=3.45), however sequencing of the underlying genes revealed no causative mutations 14 . Results Discovery GWAS stageThe GWAS discovery stage included genotype data for 6,312,048 single nucleotide polymorphisms (SNPs) after quality control and imputation (including 1,093,805 SNPs genotyped on the Illumina Omni SNP chips) in 476 MacTel cases and 1,733 controls (see Table 1 and Online Methods). This sample size was large enough to achieve power of at least 0.90 for risk variants with allele frequencies of 0.10-...

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“…A rat model for MacTel carrying an insertiondeletion mutation within the gene Crb1 has been described 70 , however we find no associated signal at this locus either.…”

Section: Discussioncontrasting

confidence: 70%

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

et al. 2017

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“…13 It seems then paradoxical that a loss of photoreceptors, which are important oxygen consumers, may lead to a proliferation of the retinal capillary toward the retinal pigment epithelium because it is likely that there is no hypoxia stimulus in these conditions. However, several animal models resulting in photoreceptor loss have also led to the abnormal vascularization of the outer retina, [14][15][16] especially in areas of photoreceptor loss or degeneration. 14,15 Moreover, a transgenic mouse model resulting in a selective ablation of Muller cells leading to photoreceptor apoptosis has also resulted in the growth of deep retinal new vessels.…”

Section: Discussionmentioning

confidence: 99%

Outer Retina Capillary Invasion and Ellipsoid Zone Loss in Macular Telangiectasia Type 2 Imaged by Optical Coherence Tomography Angiography

Gaudric

Krivosic

Tadayoni

2015

Retina

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“…Using vessels as landmark, the same region was observed with confocal microscopy and with our experimental phase microscope set with a 0. Then, we observed the retina from an 11-month-old rat presenting retinal dystrophy associated with telangiectasias [27], using a 0.65NA objective in the phase microscope ( Fig. 7D) after the immuno-staining of Iba1, the marker of microglial cells ( Fig.…”

Section: High Resolution Phase Microscopy Of Retinal Capillariesmentioning

confidence: 99%

Transscleral optical phase imaging of the human retina

et al. 2020

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The in vivo observation of the human retina at the cellular level is crucial to detect lesions before irreversible visual loss occurs, to follow the time course of retinal diseases and to evaluate and monitor the early effects of treatments. Despite the phenomenal advances in optical coherence tomography (OCT) and adaptive optics systems, in vivo imaging of several retinal cells is still elusive. Here we propose a radically different method compared to OCT, called transscleral optical phase imaging (TOPI), which allows to image retinal cells with high contrast, high resolution, and within an acquisition time suitable for clinical use. TOPI relies on high-angle oblique illumination of the retina, combined with adaptive optics, to enhance the phase contrast of transparent cells. We first present in-vivo images of retinal cells, from the retinal pigment epithelium (RPE) to the nerve and vascular layers of the retina, in eleven healthy volunteers without pupil dilation. The morphology of the cells in vivo is then compared to that of images obtained with the same technique applied on ex vivo human RPE and pig retinas. Finally, we demonstrate the ability of high resolution phase microscopy to image pericytes and microglia around rat retinal capillaries. Our results show the ability of TOPI to image and quantify retinal cells up to the RPE depth within a maximum time of 9 seconds over a field of view of 4.4 x 4.4°, opening new avenue in the in vivo exploration of the deepest layer of the retina in healthy and diseased eyes.

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A New CRB1 Rat Mutation Links Müller Glial Cells to Retinal Telangiectasia

Abstract: We have identified and characterized a spontaneous Brown Norway from Janvier rat strain (BN-J

Cited by 55 publications

References 47 publications

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

Outer Retina Capillary Invasion and Ellipsoid Zone Loss in Macular Telangiectasia Type 2 Imaged by Optical Coherence Tomography Angiography

Transscleral optical phase imaging of the human retina

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