Molecular Defects of the Cone CNG Channel Mutations

Cone vision mediated by the photoreceptor cyclic nucleotide-gated (CNG) channel activation is essential for central and color vision and vision acuity. The proper channel structure is essential for the channel function. Indeed, over 60 mutations in genes encoding the channel proteins have been linked to progressive cone dystrophy, macular degeneration, and various forms of color blindness in humans. Among these mutations, the R277C, R283W, R436W, and F547L substitutions account for 42% of all detected mutant CNG A3 genes. We hypothesize that the mutations in the channel protein interfere with the proper channel structure, which in turn hampers the channel function. It is overt that elucidating the pathogenesis of mutation is essential for the development of therapeutic strategies. Thus, the main goal of this proposal is to establish the molecular basis of the channel dysfunction caused by the mutations. The first specific aim is to explore the channel structural defects in the R277C, R283W, R436W, and F547L mutants, and the second specific aim is to determine the functional deficiency of the mutant channels. The long-term goal of this study is to develop therapeutic strategies for cone dystrophy, color blindness, and macular degeneration related to cone CNG channel mutations.