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Josseline Kaplan, Sylvain Hanein, Nathalie Delphin, Sylvie Gerber, Catherine Edelson, Nisrine Aboussair, Olivier Roche, Arnold Munnich, Isabelle Perrault, Jean-Michel Rozet; Rd3 Mutations Are Responsible For Gucy2d-like Lca. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4535.
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© ARVO (1962-2015); The Authors (2016-present)
Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration. It may present as a congenital stationary cone-rod dystrophy (LCA type I) or a progressive yet severe rod-cone dystrophy (LCA type II). Fifteen LCA genes have been identified which account for approximately 70% of cases. A unique splice-site mutation in the gene RD3 was reported to cause LCA. The purpose of this study was to assess the involvement of RD3 in a large cohort of unrelated patients affected with LCA and to look for possible genotype-phenotype correlations.
We selected 190 unrelated LCA patients originating worldwide with no mutation in known LCA genes. The two coding exons and intron-exon boundaries of the RD3 gene were screened using direct sequencing. The clinical files of patients harbouring RD3 were revisited to search for genotype-phenotype correlations.
Two original RD3 mutations were identified in 5 families originating from countries on the Shores of the Mediterranean (Algeria, Morocco n = 2, Lebanon and Turkey). The two mutations are expected to truncate severely the protein. They segregated with the disease in all five families and were not found in a control panel of 113 unrelated healthy individuals, 25/113 of who originated from Mediterranean countries. One of the two mutations segregated with the disease in 4/5 families. Segregation analysis of microsatellite markers flanking the mutation supported the hypothesis of a founder effect in 3/4 families by showing the transmission of a small common haplotype (1Mb) with the disease. Haplotype studies and Bayesian calculations suggested that the mutation occurred 100-150 generations ago. All Patients presented with LCA type I but with moderate or absent hyperopia.
This study gives support to the implication of RD3 in LCA families. Yet, the identification of homozygous mutations in consanguineous families originating from closely-related populations suggests that only rare population-specific mutations might exist. All patients presented with LCA type 1. Interestingly, this phenotype was originally described in patients with mutations in the gene encoding GUCY2D which trafficking in photoreceptors depends on RD3. Finally, none of the patients (2-31 yrs) had renal failure, neurological symptoms or mental retardation. Owing to the retina-specific pattern of expression of RD3, it is likely that the disease may remain restricted to the retina.
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