Impaired Association of Retinal Degeneration-3 with Guanylate Cyclase-1 and Guanylate Cyclase Activating Protein-1 Leads to Leber Congenital Amaurosis-1 [Molecular Bases of Disease]

December 4th, 2014 by Zulliger, R., Naash, M. I., Rajala, R. V. S., Molday, R. S., Azadi, S.

One-fifth of all cases of Leber Congenital Amaurosis (LCA) are Type 1, a severe form of retinal dystrophy caused by loss-of-function mutations in guanylate cyclase1 (GC1), a key member of the phototransduction cascade involved in modulating the photocurrents. Although GC1 has been studied for some time, the mechanisms responsible for its regulation and membrane targeting are not fully understood. We reported earlier that retinal degeneration 3 (RD3) protein interacts with GC1 and promotes its targeting to the photoreceptor outer segments (POS). Here we extend our studies to show direct association between RD3 and guanylate cyclase activating protein1 (GCAP1) and that this functional interaction is important for GC1 targeting to POS. We also show that most LCA1-causing mutations in GC1 result in loss of its interaction with RD3 or being targeted to the plasma membrane. Our data suggest that GC1, GCAP1, and RD3 form a complex in the endoplasmic reticulum that target GC1 to POS. Interruption of this assembly is likely the underlying mechanism for a subset of LCA1. This study offers insights for the development of therapeutic strategies to treat this severe form of blindness.
  • Posted in Journal of Biological Chemistry, Publications
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