Spectrum of retGC1 mutations in Leber's congenital amaurosis

Eur J Hum Genet. 2000 Aug;8(8):578-82. doi: 10.1038/sj.ejhg.5200503.


Leber's congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies responsible for congenital blindness. Genetic heterogeneity of LCA has been suspected since the report by Waardenburg of normal children born to affected parents. In 1995 we localised the first disease causing gene, LCA1, to chromosome 17p13 and confirmed the genetic 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 with LCA. We found 22 different mutations in 24 unrelated families originating 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 establish. 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 consistent light exposure during photoreceptor development, explaining the severity of the visual disorder at birth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blindness / congenital*
  • Blindness / enzymology
  • Blindness / genetics
  • Chromosomes, Human, Pair 17
  • Cyclic GMP / metabolism
  • Female
  • Genetic Heterogeneity
  • Genotype
  • Guanylate Cyclase / genetics*
  • Humans
  • Male
  • Mutation*
  • Optic Atrophies, Hereditary / enzymology
  • Optic Atrophies, Hereditary / genetics*
  • Pedigree
  • Phenotype
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Receptors, Cell Surface*
  • Rod Cell Outer Segment / enzymology*
  • Sequence Analysis, DNA


  • Receptors, Cell Surface
  • guanylate cyclase 1
  • Guanylate Cyclase
  • Cyclic GMP