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Abouzeid H.,University of Lausanne | Gawdat G.,Cairo University | de Preux A.-S.,University of California at San Francisco | Xiao T.,University of California at San Francisco | And 7 more authors.
Human Molecular Genetics | Year: 2013

The major active retinoid, all-trans retinoic acid, has long been recognized as critical for the development of several organs, including the eye. Mutations in STRA6, the gene encoding the cellular receptor for vitamin A, in patients with Matthew-Wood syndrome and anophthalmia/microphthalmia (A/M), have previously demonstrated the importance of retinol metabolism in human eye disease.Weused homozygosity mapping combined with next-generation sequencing to interrogate patients with anophthalmia and microphthalmia for new causative genes.We used whole-exome and whole-genome sequencing to study a family with two affected brothers with bilateral A/M and a simplex case with bilateral anophthalmia and hypoplasia of the optic nerve and optic chiasm. Analysis of novel sequence variants revealed homozygosity for two nonsense mutations in ALDH1A3, c.568A>G, predicting p.Lys190*, in the familial cases, and c.1165A>T, predicting p.Lys389*, in the simplex case. Both mutations predict nonsense-mediated decay and complete loss of function. We performed antisense morpholino (MO) studies in Danio rerio to characterize the developmental effects of loss of Aldh1a3 function. MO-injected larvae showed a significant reduction in eye size, and aberrant axonal projections to the tectum were noted. We conclude that ALDH1A3 loss of function causes anophthalmia and aberrant eye development in humans and in animal model systems. © The Author 2013. Published by Oxford University Press. All rights reserved.


Michaelides M.,University College London | Michaelides M.,Moorfields Eye Hospital | Gaillard M.-C.,Hopital Ophtalmique Jules Gonin | Escher P.,Institute Of Recherche En Ophtalmologie | And 22 more authors.
Investigative Ophthalmology and Visual Science | Year: 2010

PURPOSE. To characterize in detail the phenotype of five unrelated families with autosomal dominant bull's eye maculopathy (BEM) due to the R373C mutation in the PROM1 gene. METHODS. Forty-one individuals of five families of Caribbean (family A), British (families B, D, E), and Italian (family C) origin, segregating the R373C mutation in PROM1, were ascertained. Electrophysiological assessment, fundus autofluorescence (FAF) imaging, fundus fluorescein angiography (FFA), and optical coherence tomography (OCT) were performed in available subjects. Mutation screening of PROM1 was performed. RESULTS. The R373C mutant was present heterozygously in all affected patients. The age at onset was variable and ranged between 9 and 58 years, with most of the individuals presenting with reading difficulties. Subjects commonly had a mild to moderate reduction in visual acuity except for members of family C who experienced markedly reduced central vision. The retinal phenotype was characterized by macular dystrophy, with retinal pigment epithelial mottling in younger subjects, progressing to typical BEM over time, with the development of macular atrophy in older patients. In addition, all members of family C had typical features of RP. The electrophysiological findings were variable both within and between families. CONCLUSIONS. Mutations in PROM1 have been described to cause a severe form of autosomal recessive RP in two families of Indian and Pakistani descent. The results of this study have demonstrated that a distinct redundant PROM1 mutation (R373C) can also produce an autosomal dominant, fully penetrant retinopathy, characterized by BEM with little inter- and intrafamilial variability, and retinal dystrophy with variable rod or rod-cone dysfunction and marked intra- and interfamilial variability, ranging from isolated maculopathy without generalized photoreceptor dysfunction to maculopathy associated with very severe rod-cone dysfunction. © Association for Research in Vision and Ophthalmology.


Mataftsi A.,Jules Gonin Eye Hospital | Mataftsi A.,Aristotle University of Thessaloniki | Zografos L.,Jules Gonin Eye Hospital | Balmer A.,Jules Gonin Eye Hospital | And 8 more authors.
Ophthalmic Genetics | Year: 2012

Purpose: To report the lethal course of malignant transformation of retinoma in an adult. Methods: Case report. A 40-year-old patient presented with retinoma in his right eye and retinoblastoma in his left eye. Enucleation was recommended but refused and the patient received whole eye radiotherapy elsewhere. Five years later he presented again, with temporal hemianopsia of the left eye secondary to chiasmatic invasion. Results: Diagnosis of retinoblastoma infiltration was confirmed by stereotactic biopsy of the chiasmatic lesion. Treatment with intravenous and intrathecal chemotherapy led to partial remission, and was followed by stereotactic irradiation of the chiasmatic mass and right optic nerve. The left eye was enucleated. Death occurred one year later due to cerebrospinal fluid metastases. Conclusion: Extraocular extension of retinoblastoma diagnosed in adulthood has never, to our knowledge, been reported. This case stresses the importance of lifelong retinoma monitoring and the necessity for radical treatment in the event of malignant transformation. © 2012 Informa Healthcare USA, Inc.


Chiquet C.,Joseph Fourier University | Tonini M.,Joseph Fourier University | Drillat P.,Etablissement Francais du Sang | Gaudry V.V.M.,Joseph Fourier University | And 3 more authors.
Retina | Year: 2010

Purpose: To evaluate the effect of hemodilution on subfoveal choroidal blood flow in the human eye with or without retinal vein occlusion. Methods: Choroidal blood flow was measured using laser Doppler flowmetry in 28 patients with retinal vein occlusion in 1 eye. Isovolemic hemodilution was performed when hematocrit was >35%. Laser Doppler flowmetry parameters, velocity, volume, and flow were measured in both eyes in 4 sessions: 1 hour before and 1 hour after the first hemodilution on Day 1 and Day 7. Results: Hematocrit decreased significantly by 23.7%, 19.8%, and 16.1% in the first hour, on the first day, and the seventh day after hemodilution, respectively (P < 0.001). The ocular perfusion pressure of the healthy eye and the eye with retinal vein occlusion decreased by 7.7% and 7.2% after 1 hour and by 5.3% and 4.7% 1 day after hemodilution, respectively (P < 0.01). After hemodilution, subfoveal choroidal blood velocity, volume, flow, and vascular resistance did not significantly change in either eye. Conclusion: Laser Doppler flowmetry measurement in the subfoveal choroid is a feasible technique for blood flow assessment in patients with retinal vein occlusion. A substantial change of hematocrit after isovolemic hemodilution does not lead to a significant change in choroidal blood flow. Vascular regulation is expected to keep blood flow constant and needs to be further explored. Copyright © by Ophthalmic Communications Society, Inc.


Luder H.U.,University of Zürich | Gerth-Kahlert C.,University of Zürich | Ostertag-Benzinger S.,University of Zürich | Ostertag-Benzinger S.,Private Practice | And 3 more authors.
PLoS ONE | Year: 2013

Jalili syndrome denotes a recessively inherited combination of an eye disease (cone-rod dystrophy) and a dental disorder (amelogenesis imperfecta), which is caused by mutations in the CNNM4 gene. Whereas the ophthalmic consequences of these mutations have been studied comprehensively, the dental phenotype has obtained less attention. A defective transport of magnesium ions by the photoreceptors of the retina is assumed to account for the progressive visual impairment. Since magnesium is also incorporated in the mineral of dental hard tissues, we hypothesized that magnesium concentrations in defective enamel resulting from mutations in CNNM4 would be abnormal, if a similar deficiency of magnesium transport also accounted for the amelogenesis imperfecta. Thus, a detailed analysis of the dental hard tissues was performed in two boys of Kosovan origin affected by Jalili syndrome. Retinal dystrophy of the patients was diagnosed by a comprehensive eye examination and full-field electroretinography. A mutational analysis revealed a c.1312 dupC homozygous mutation in CNNM4, a genetic defect which had already been identified in other Kosovan families and putatively results in loss-of-function of the protein. The evaluation of six primary teeth using light and scanning electron microscopy as well as energy-dispersive X-ray spectroscopy showed that dental enamel was thin and deficient in mineral, suggesting a hypoplastic/hypomineralized type of amelogenesis imperfecta. The reduced mineral density of enamel was accompanied by decreased amounts of calcium, but significantly elevated levels of magnesium. In dentin, however, a similar mineral deficiency was associated with reduced magnesium and normal calcium levels. It is concluded that the c.1312 dupC mutation of CNNM4 results in mineralization defects of both enamel and dentin, which are associated with significantly abnormal magnesium concentrations. Thus, we could not disprove the hypothesis that a disrupted magnesium transport is involved in the development of the dental abnormalities observed in Jalili syndrome. © 2013 Luder et al.


Barthelmes D.,University of Zürich | Bosch M.M.,University of Zürich | Merz T.M.,University of Bern | Petrig B.L.,Institute Of Recherche En Ophtalmologie | And 9 more authors.
PLoS ONE | Year: 2011

Background: Retinal hemorrhages have been described as a component of high altitude retinopathy (HAR) in association with altitude illness. In this prospective high altitude study, we aimed to gain new insights into the pathophysiology of HAR and explored whether HAR could be a valid early indicator of altitude illness. Methodology/Principal Findings: 28 mountaineers were randomly assigned to two ascent profiles during a research expedition to Mt. Muztagh Ata (7546 m/24,751 ft). Digital fundus photographs were taken prior to expedition at 490 m (1,607 ft), during expedition at 4497 m (14,750 ft = base camp), 5533 m (18,148 ft), 6265 m (20,549 ft), 6865 m (22,517 ft) and 4.5 months thereafter at 490 m. Number, size and time of occurrence of hemorrhages were recorded. Oxygen saturation (SpO2) and hematocrit were also assessed. 79% of all climbers exhibited retinal hemorrhages during the expedition. Number and area of retinal bleeding increased moderately to medium altitudes (6265 m). Most retinal hemorrhages were detected after return to base camp from a high altitude. No post-expeditional ophthalmic sequelae were detected. Significant negative (SpO2 Beta: -0.4, p<0.001) and positive (hematocrit Beta: 0.2, p = 0.002, time at altitude Beta: 0.33, p = 0.003) correlations with hemorrhages were found. Conclusions/Significance: When closely examined, a very large amount of climbers exhibit retinal hemorrhages during exposure to high altitudes. The incidence of retinal hemorrhages may be greater than previously appreciated as a definite time lag was observed between highest altitude reached and development of retinal bleeding. Retinal hemorrhages should not be considered warning signs of impending severe altitude illness due to their delayed appearance. © 2011 Barthelmes et al.


Falsini B.,University Cattolica ore | Riva C.E.,University of Lausanne | Salgarello T.,University Cattolica ore | Logean E.,Institute Of Recherche En Ophtalmologie | And 2 more authors.
Optical Engineering | Year: 2014

We evaluated in ocular hypertension (OHT) and early glaucoma (EOAG) patients the optic nerve head (ONH) blood flow response (RFonh) to chromatic equiluminant flicker. This stimulus generates neural activity dominated by the parvo-cellular system. Eleven EOAG, 20 OHT patients, and 8 age-matched control subjects were examined. The blood flow (Fonh) at the neuroretinal rim was continuously monitored by laser Doppler flowmetry before, during, and after a 60-s exposure to a 4 Hz, red-green equiluminant flicker stimulus RFonh was expressed as percentage Fonh-change during the last 20 s of flicker relative to baseli Responses were collected at a number of temporal sites. The highest RFonh value was used for subsequent analysis. As compared to controls, both OHT and EOAG patients showed a decrease.


Allaman-Pillet N.,Institute Of Recherche En Ophtalmologie | Oberson A.,Institute Of Recherche En Ophtalmologie | Bustamante M.,Institute Of Recherche En Ophtalmologie | Tasinato A.,Institute Of Recherche En Ophtalmologie | And 3 more authors.
Experimental Eye Research | Year: 2015

BIGH3 is a secreted protein, part of the extracellular matrix where it interacts with collagen and integrins on the cell surface. BIGH3 can play opposing roles in cancer, acting as either tumor suppressor or promoter, and its mutations lead to different forms of corneal dystrophy. Although many studies have been carried out, little is known about the physiological role of BIGH3. Using the cre-loxP system, we generated a mouse model with disruption of the Bigh3 genomic locus. Bigh3 silencing did not result in any apparent phenotype modifications, the mice remained viable and fertile.We were able to determine the presence of BIGH3 in the retinal pigment epithelium (RPE). In the absence of BIGH3, a transient decrease in the apoptotic process involved in retina maturation was observed, leading to a transient increase in the INL thickness at P15. This phenomenon was accompanied by an increased activity of the pro-survival ERK pathway. © 2015 Elsevier Ltd.


PubMed | University of Lausanne, Institute Of Recherche En Ophtalmologie and Ecole Polytechnique Federale de Lausanne
Type: | Journal: Experimental eye research | Year: 2015

BIGH3 is a secreted protein, part of the extracellular matrix where it interacts with collagen and integrins on the cell surface. BIGH3 can play opposing roles in cancer, acting as either tumor suppressor or promoter, and its mutations lead to different forms of corneal dystrophy. Although many studies have been carried out, little is known about the physiological role of BIGH3. Using the cre-loxP system, we generated a mouse model with disruption of the Bigh3 genomic locus. Bigh3 silencing did not result in any apparent phenotype modifications, the mice remained viable and fertile. We were able to determine the presence of BIGH3 in the retinal pigment epithelium (RPE). In the absence of BIGH3, a transient decrease in the apoptotic process involved in retina maturation was observed, leading to a transient increase in the INL thickness at P15. This phenomenon was accompanied by an increased activity of the pro-survival ERK pathway.

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