In order to gain insight into the structure-function relationship of retinal disease-causing mutations in GC-E, we investigated three critical parameters of the enzymatic activity profile of GC-E: (1) increase of GC-E activity in the presence of Ca2+-free/Mg2+-bound GCAP1 and GCAP2; (2) inhibitory effect of RD3, when GC-E is in the activated state in complex with GCAP1 or GCAP2; and (3) Ca2+-sensitive activation profile of GC-E. Here, GUCA1B is linked to Abnormal retinal morphology.