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Abstract

Abstract 

  1. Leber congenital amaurosis (LCA) (MIM 204000) is characterized by severe or complete loss of visual function apparent early in infancy with failure to follow visual stimuli, nystagmus, and roving eye movements. Affected individuals have an extinguished electroretinogram and eventually develop abnormalities of the ocular fundus including a pigmentary retinopathy. Although many LCA patients have no additional abnormalities, in some there is associated mental retardation. LCA is inherited as an autosomal recessive trait. Aside from helping the patient adapt to life with no visual function, there is no treatment.

  2. The LCA phenotype is genetically heterogeneous, with mutations in at least three genes causing the disorder. LCA1 maps to 17p13 and encodes retGC-1, a photoreceptor-specific guanylate cyclase. LCA2 maps to 1p31 and encodes RPE65, a 61-kDa retinal pigment epithelium (RPE)-specific microsomal protein. Mutations at this locus also have been shown to cause childhood-onset severe retinal dystrophy (CSRD). LCA3 maps to 19q13.3 and encodes CRX, a homeodomain transcription factor that is a positive activator of several photoreceptor-specific genes.

  3. Animal models of LCA include the rd/rd chick, in which blindness precedes photoreceptor degeneration. The responsible gene (GC1) encodes a guanylate cyclase with 61 percent amino acid identity to mammalian guanylate cyclase 1, and a deletion/insertion mutant allele has been identified in the rd/rd chick. Additionally, a mouse model with targeted disruption of the murine guanylate cyclase gene (GCE) has been produced. These mice exhibit an early loss of the cone ERG followed later by loss of the rod ERG. Finally, a mouse model with targeted disruption of the RPE65 gene has been produced. These animals have a severely abnormal dark-adapted ERG and subtle morphologic abnormalities of the photoreceptor outer segments.

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