Visual consequences of molecular changes in the guanylate cyclase-activating protein.

ABSTRACT

PURPOSE: We characterized and modeled changes in visual performance associated with a Tyr99Cys mutation in guanylate cyclase-activating protein-1 (GCAP1) in four family members aged between 39 and 55 years old. Guanylate cyclase and its activating protein are molecules in the visual transduction pathway that restore cyclic GMP (cGMP) following its light-activated hydrolysis. The mutation causes an excess of cGMP in the dark and results in progressive photoreceptor loss. METHODS: L-cone temporal acuity was measured as a function of target irradiance, and L-cone temporal contrast sensitivity was measured as a function of temporal frequency. RESULTS: All four mutant GCAP1 family members showed sensitivity or acuity losses relative to normal observers. The data for the youngest family member are consistent with an abnormal speeding up of the visual response relative to that in normals, but those for the older members showed a progressively higher-frequency sensitivity loss consistent with a slowing down of their response. CONCLUSIONS: The speeding up of the visual response in the youngest observer is consistent with the Tyr99Cys mutation that results in the more rapid replacement of cGMP after light exposure and, thus, in a reduction of temporal integration and relative improvement in high-frequency sensitivity compared to normals. The high-frequency losses in the older observers are consistent with their vision being limited by the interposition of some sluggish process. This might result from some residual or malfunctioning molecular process limiting transduction within damaged photoreceptors or from an active or passive postreceptoral reorganization caused by the paucity of functioning photoreceptors.