Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D.

摘要: Abstract The GUCY2D gene encodes for the photoreceptor guanylate cyclase GC-E that synthesizes intracellular messenger of excitation cGMP and is regulated by Ca2+-sensor proteins named cyclase-activating (GCAPs). Over 140 disease-causing mutations have been described so far in GUCY2D, 88% which cause autosomal recessive Leber congenital amaurosis (LCA) while heterozygous missense dominant cone-rod degeneration (adCRD). Mutations are one major causes all LCA cases adCRD. A single amino acid, arginine at position 838, likely to be most sensitive as four two complex were reported affect R838. biochemical effect 45 GC-E variants was studied showing a clear genotype-phenotype correlation: LCA-causing either show reduced ability or complete inability synthesize from GTP, CRD-causing functional, but shift Ca2+-sensitivity − GCAP complex. Eight animal models retinal deficiency including knockout (KO) mouse chicken models. These used augmentation therapy yielded promising results. Here we integrate available information on genetics, biochemistry phenotype related mutations. data clearly mutation type (missense versus null) localization (dimerization domain other protein domains) correlated with pattern inheritance, impact enzymatic function phenotype. Such correlation unique many disease genes variable phenotypes lack assays.