Abstract
Leber's congenital amaurosis (LCA, MIM 2040001), the earliest and most severe form of inherited retinopathy, accounts for at least 5% of all inherited retinal dystrophies2,3. This autosomal recessive condition is usually recognized at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus and extinguished electroretinogram (ERG4). Nystagmus (pendular type) and characteristic eye poking are frequently observed in the first months of life (digitoocular sign of Franceschetti5). Hypermetropia and keratoconus frequently develop in the course of the disease6,7. The observation by Waardenburg8 of normal children born to affected parents supports the genetic heterogeneity of LCA. Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photore-ceptors or extremely early degeneration of cells that have developed normally9. We have recently mapped a gene for LCA to chromosome 17p13.1 (LCA1) by homozygosity mapping in consanguineous families of North African origin and provided evidence of genetic heterogeneity in our sample, as LCA1 accounted for 8/15 LCA families in our series10,11. Here, we report two missense mutations (F589S) and two frameshift mutations (nt 460 del C, nt 693 del C) of the retinal guanylate cyclase (RETGC, GDB symbol GUC2D) gene in four unrelated LCA1 probands of North African ancestry and ascribe LCA1 to an impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels.
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Perrault, I., Rozet, J., Calvas, P. et al. Retinal–specific guanylate cyclase gene mutations in Leber's congenital amaurosis. Nat Genet 14, 461–464 (1996). https://doi.org/10.1038/ng1296-461
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DOI: https://doi.org/10.1038/ng1296-461
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