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Macular dystrophy leads to progressive loss of central vision and shows symptoms similar to age-related macular degeneration. Genetic screening of patients diagnosed with macular dystrophy disclosed a novel mutation in the  GUCA1A  gene, namely a c.526C &gt; T substitution leading to the amino acid substitution p.L176F in the guanylate cyclase-activating protein 1 (GCAP1). The same variant was found in three families showing an autosomal dominant mode of inheritance. For a full functional characterization of the L176F mutant we expressed and purified the mutant protein and measured key parameters of its activating properties, its Ca 2+ /Mg 2+ -binding, and its Ca 2+ -induced conformational changes in comparison to the wildtype protein. The mutant was less sensitive to changes in free Ca 2+ , resulting in a constitutively active form under physiological Ca 2+ -concentration, showed significantly higher activation rates than the wildtype (90-fold versus 20-fold) and interacted with an higher apparent affinity with its target guanylate cyclase. However, direct Ca 2+ -binding of the mutant was nearly similar to the wildtype; binding of Mg 2+  occurred with higher affinity. We performed molecular dynamics simulations for comparing the Ca 2+ -saturated inhibiting state of GCAP1 with the Mg 2+ -bound activating states. The L176F mutant exhibited significantly lower flexibility, when three Ca 2+  or two Mg 2+  were bound forming probably the structural basis for the modified GCAP1 function.

Dysfunction of cGMP signalling in photoreceptors by a macular dystrophy-related mutation in the calcium sensor GCAP1