Guanylate cyclase activating proteins, guanylate cyclase and disease

A range of cone and cone-rod dystrophies (CORD) have been observed in man, caused by mutations in retinal guanylate cyclase 1 (RetGC1) and guanylate cyclase activating protein 1 (GCAP 1). The CORD causing mutations in RetGC1 are located at a mutation "hot spot" within the dimerisation domain, where R838 is the key residue. Three disease causing mutations have been found in human GCAP1, resulting in cone or cone-rod degeneration. All three mutations are dominant in their effect although the mechanism by which the P50L mutation exerts its influence remains unclear although it might act due to a haplo-insufficiency, arising from increased susceptibility to protease activity and increased thermal instability. In contrast, loss of Ca2+ sensitivity appears to be the main cause of the diseased state for the Y99C and E155G mutations. The cone and cone-rod dystrophies that are caused by mutations in RetGC1 or GCAP1 arise from a perturbation of the delicate balance of Ca2+ and cGMP within the photoreceptor cells and it is this disruption that is believed to cause cell death. The diseases caused by mutations in RetGC1 and GCAP1 prominently affect cones, consistent with the higher concentrations of these proteins in cone cells.