6533b858fe1ef96bd12b6a72

RESEARCH PRODUCT

Caractérisation des effets ophtalmiques du syndrome de Cohen chez des souris VPS13B-/- et identification des mécanismes moléculaires impliqué dans la pathogenèse.

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Cohen Syndrome (CS) is a rare autosomal recessive disease caused by variations in the gene coding for the vacuolar tri-vacuolar protein 13B (VPS13B or COH1). CS patients have common features including typical facial appearance, neutropenia, abnormal trunk fat distribution, microcephaly, myopia and retinal damage. My thesis project aimed to characterize the ophthalmologic phenotype of a mouse model Vps13bEx3/Ex3 to determine the molecular mechanisms involved in the development of CS retinopathy.First, we showed that Vps13bEx3/Ex3 mice develop a cataract between 2 and 3 months. Disorganization of the fibrous cells of the crystalline lens and their differentiation into mesenchymal cells were observed. At a more advanced stage, the external membrane of the crystalline lens is ruptured and the cortical and nuclear part of the crystalline lens separates. After the onset of cataract, the retina shows deformations characterized by thinning and deformation of its various layers which can lead to retinal folds 50 to 500µm long. There is also a strong proliferation of microglial cells as well as astrogliosis. The appearance of cataract in our model has led to an exhaustive review of the literature showing that cataract is present in 85% of patients at 40 years old and not related to retinopathy.We then showed a modification of the ocular phenotype in the presence of the Crb1Rd8 mutation. Crb1 is a transmembrane protein whose Rd8 variation leads to retinal disorganization. We have created cohorts of all possible Vps13b/Crb1 genotypes. Our preliminary analyses show early retinal dystrophy in mice Vps13bEx3/Ex3 Crb1Rd8/+, suggesting that Vps13b could be a Crb1 modifier gene. Molecular mechanisms that could lead to the appearance of SC retinopathy have been studied in Vps13bEx3/Ex3Crb1+/+ mice. The structure of the retina and these different cell populations were studied but did not reveal any abnormalities before the onset of the cataract. However, the study of inflammatory mechanisms showed an increase in sensitivity to IL6 in the retina of our model. This mechanism could be involved in the development of SC retinopathy. As the ocular phenotype is strongly decreased in mice Vps13bEx3/Ex3 Crb1+/+,the impact of environmental factors, especially light, has also been studied and shows that when subjected to high light intensity, mice develop retinopathies.In parallel, we have studied the ophthalmological characteristics of our Dijon cohort mainly using OCT. This study reveals (i) that macular edema is a frequent symptom of SC which remains relatively stable over time and (ii) that the onset of retinopathy is independent of that of cataract.Consequently, my PhD work has allowed to characterize the ophthalmic attacks of our Vps13bEx3/Ex3 mouse model and will allow to deepen the mechanistic knowledge of retinopathy and cataract of the CS, and could allow to develop a therapeutic target or prevention strategies for these ophthalmic lesions.