Spectrum of retGC1 mutations in Leber's congenital amaurosis

Leber's congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies responsible for congenital blindness. Gen etic heterogeneity of LCA has been suspected since the report by Waardenbur g of normal children born to affected parents. In 1995 we localised the fir st disease causing gene, LCA1, to chromosome 17p13 and confirmed the geneti c heterogeneity. In 1996 we ascribed LCA1 to mutations in the photoreceptor -specific guanylate cyclase gene (retGC1). Here, we report on the screening of the whole coding sequence of the retGC1 gene in 118 patients affected w ith LCA. We found 22 different mutations in 24 unrelated families originati ng from various countries of the world. It is worth noting that all retGC1 mutations consistently caused congenital cone-rod dystrophy in our series, confirming the previous genotype-phenotype correlations we were able to est ablish. RetGC1 is an essential protein implicated in the phototransduction cascade, especially in the recovery of the dark state after the excitation process of photoreceptor cells by light stimulation. We postulate that the retGC1 mutations hinder the restoration of the basal level of cGMP of cone and rod photoreceptor cells, leading to a situation equivalent to consisten t light exposure during photoreceptor development, explaining the severity of the visual disorder at birth.