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GCAP1 and GCAP2 bound to different regions on the target guanylate cyclase type 1 with submicromolar affinity (apparent KD-values of 663 +/- 121 nM and 231 +/- 63 nM for Ca(2+)-free GCAP1 and GCAP2, respectively).
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Allosteric communication pathways routed by Ca(2+)/Mg(2+) exchange in GCAP1 selectively switch target regulation modes.
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GUCA1A mutations could cause significant variability in maculopathies, including central areolar choroidal dystrophy, which represents a severe pattern of maculopathy.
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The two novel mutations described in this study are associated with distinct phenotypes, macular dystrophy for p.Val101del and cone dystrophy for p.Asp148Glu, with no intrafamilial phenotypic heterogeneity.
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GCAP1 mutation is associated with macular dystrophy.
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Retinal dystrophy-associated missense mutations (L84F, I107T) in GUCA1A with distinct molecular properties result in a similar aberrant regulation of the retinal guanylate cyclase.
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Dimerization domain of RETGC1 is an essential part of GCAP1 and GCAP2 binding interface.
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The GCAP1 and GCAP2 binding site(s) overlaps within the kinase homology and/or dimerization domains of retinal GC1.
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GUCA1A and GUCY2D mutations are both accompanied by similar pattern of generalized cone dysfunction with a tendency to less involvement of the rod photoreceptors and a less severe phenotype in patients with GUCA1A.
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RetGC1 activation by GCAP1 involves establishing a tight complex through the binding patch with an additional activation step involving Met-26, Lys-85, and Trp-94.
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All four mutant GCAP1 family members showed sensitivity or acuity losses relative to normal observers.
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we predicted that either haploinsufficiency or dominant-negative effect accompanied by creation of a novel function for the mutant protein is a possible mechanism of the retinal degeneration due to c.250C>T and c.320T>C of the GUCA1A
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Patients with autosomal dominant cone-rod dystrophy caused by a D100G mutation in GUCA1A exhibit progressive vision loss early within the first decade of life identifiable by distinct ERG.
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the GUCA1A mutation only contributes to a small portion of CORD in people of Chinese descent.
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Stimulation by GCAP increases the maximal velocity (Vmax) for retinal guanylyl cyclase activation up to 100-fold in HEK293 cell membranes.
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The consequences of specific mutations on GCAP1 structure and GC stimulation, are described.
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role in rescuing cone recovery kinetics in knockout mice
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The dynamic range for recombinant photoreceptor guanylyl cyclase-1 regulation by calcium (Ca2+)/GCAP1 is determined by both the affinity of GCAP1 for Ca2+ and relative affinities of the effector enzyme for the Ca2+-free versus Ca2+-loaded GCAP1.
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A novel GCAP1 mutation, I143NT, caused a form of autosomal dominant cone degeneration that destroys foveal cones by mid-life but spares some cones in the peripheral retina up to 75 years.
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A novel L151F missense mutation in the EF4 high affinity Ca2+ binding site of GCAP1 is linked to adCD (autosomal dominant cone dystrophy) in a large pedigree.
