Guanylate Cyclase - Mutations

Mutations

Cone dystrophy (COD) is a retinal degradation of photoreceptor function where cone function is lost at the onset of the dystrophy but rod function is preserved until almost the end. COD has been linked to several genetic mutations including mutations in the guanylate cyclase activator 1A (GUCA1A) and guanylate cyclase 2D (GUY2D) among other enzymes. Specifically, GUY2D codes for RETGC-1, which is involved in cone adaptation and photoreceptor sensitivity by synthesizing cGMP. Low concentrations of calcium cause the dimerization of RETGC-1 proteins through stimulation from guanylyl cyclase activating protens (GCAP). This process happens at amino acids 817-857 and mutations in this region increase RETGC-1 affinity for GCAP. This works to alter the calcium sensitivity of the neuron by allowing mutant RETGC-1 to be activated by GCAP at higher calcium levels than the wild-type. Because RETGC-1 produces cGMP which keeps cyclic gated nucleotide channels open allowing the influx of calcium, this mutation causes extremely high intracellular calcium levels. Calcium, which plays many roles in the cell and is tightly regulated, disrupts the membrane when it appears in excess. Additionally, calcium is also linked to apoptosis by causing the release of cytochrome c. Therefore, mutations in the RETGC-1 can cause COD by increasing intracellular calcium levels and stimulating cone photoreceptor death.