Cone opsin determines the time course of cone photoreceptor degeneration in Leber congenital amaurosis
T Zhang, N Zhang, W Baehr… - Proceedings of the …, 2011 - National Acad Sciences
Proceedings of the National Academy of Sciences, 2011•National Acad Sciences
Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal recycling
and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early
childhood. We used Lrat−/−, a murine model for LCA, to investigate the mechanism of rapid
cone degeneration. Although both M and S cone opsins mistrafficked as reported previously,
mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lrat−/−
cones before the onset of massive ventral/central cone degeneration. As the ventral and …
and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early
childhood. We used Lrat−/−, a murine model for LCA, to investigate the mechanism of rapid
cone degeneration. Although both M and S cone opsins mistrafficked as reported previously,
mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lrat−/−
cones before the onset of massive ventral/central cone degeneration. As the ventral and …
Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal recycling and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early childhood. We used Lrat−/−, a murine model for LCA, to investigate the mechanism of rapid cone degeneration. Although both M and S cone opsins mistrafficked as reported previously, mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lrat−/− cones before the onset of massive ventral/central cone degeneration. As the ventral and central retina express higher levels of S-opsin than the dorsal retina in mice, our results may explain why ventral and central cones degenerate more rapidly than dorsal cones in Rpe65−/− and Lrat−/− LCA models. In addition, human blue opsin and mouse S-opsin, but not mouse M-opsin or human red/green opsins, aggregated to form cytoplasmic inclusions in transfected cells, which may explain why blue cone function is lost earlier than red/green-cone function in patients with LCA. The aggregation of short-wavelength opsins likely caused rapid cone degenerations through an endoplasmic reticulum stress pathway, as demonstrated in both the Lrat−/− retina and transfected cells. Replacing rhodopsin with S-opsin in Lrat−/− rods resulted in mislocalization and aggregation of S-opsin in the inner segment and the synaptic region of rods, ER stress, and dramatically accelerated rod degeneration. Our results demonstrate that cone opsins play a major role in determining the degeneration rate of photoreceptors in LCA.
National Acad Sciences