Abstract
Inherited retinal disorders are a clinically and genetically heterogeneous group.They are progressive Mendelian genetic diseases that cause dysfunction then cell death, including photoreceptors and retinal pigment epithelium cells (RPE). Cells death is accompanied by intra-retinal pigment deposits generally located in the retinal periphery, thus constituting the majority subgroup of pigment retinitis (RP). More rarely, lesions of various appearance affecting the macula, central region of the retina, forming the subgroup of macular dystrophies (MD). These neurodegeneration gradually lead to more or less complete blindness, without therapeutic. Despite the identification of over 90 genes associated with RP, conventional genetic testing (Sanger, panel) fails to detect a molecular diagnosis in about one third of RP patients. The identification of new genes is of major interest for understanding the disease, for establishing phenotype / genotype correlations, for improving genetic counseling, and finally for defining therapeutic pathways.For this purpose, the genetic study of a large family with autosomal dominant RP without molecular diagnosis was carried out by exome sequencing. NGS approach made it possible to identify a pathogenic splicing variant in IMPG1, a gene never described in RP. IMPG1 had been previously associated with vitelliform macular dystrophy (VMD). A complementary genetic analysis on multicentric cohorts of patients with RP or DMV, allowed to identify six additional pathogenic variants (including five new variants), in 10 other families with dominant or recessive forms of RP or DMV.We followed our study performing in vivo functional study in medaka fish, then in mice by invalidating the orthologous gene of the human IMPG1. The fish study, the use of morpholino, showed that the Impg1 gene product plays an important role, in the early development and maintenance of the biological functions of the retina. The length of the outer segments of rod and cone photoreceptors were reduced by 20% and 90% respectively. However, the invalidation of Impg1 expression is transient in fish and very limited phenotype analyzes.Impg1-/- mice helped to perform more complete visual functional studies and to examine their evolution over a long period. Impg1-/- mice show an abnormal accumulation of autofluorescent deposits visible with fundoscope and optical coherence tomography (OCT) from 9 months of age. Electroretinogram (ERG) is reduced by about 20%. The electron microscopy of mice retinas makes it possible to highlight the precise localization of the anomalies, within interphotoreceptor matrix. The mouse animal model seems to reproduce DMV phenotype while the fish model shows similarities with RP.To summarize, this thesis work allows us to extend the clinical spectrum of disorders associated with mutations in IMPG1 gene. Two new diagnoses must therefore be added to VMD: autosomal dominant and recessive RP. The animal models developed allow a better understanding of the cellular mechanisms affected by invalidation of the IMPG1 gene. However, the mechanism explaining macular or peripheral involvement in humans, as well as the different modes of transmission and penetrance variations have not yet been elucidated.