Function of C8ORF37 in Photoreceptors

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Project Summary Rods and cones are photoreceptors responsible for dim light vision and day light color vision, respectively. The outer segment (OS) of rods and cones is an enlarged cilium for phototransduction containing many tightly- aligned membrane discs. During development, the OS proteins are synthesized in the inner segment and transported to the distal end of the connecting cilium. These OS proteins subsequently contribute to the morphogenesis of OSs containing well-organized membrane discs. Defects in this process are associated with various inherited retinal degenerative diseases. The long-term goal of our research is to understand the mechanism underlying OS disc morphogenesis through investigating genes associated with inherited retinal degenerations. Retinitis pigmentosa (RP) is the most common inherited retinal degeneration with a prevalence of 1 in 4,000 people. This disease affects rods and subsequently cones. Cone-rod dystrophy (CRD) is another form of inherited retinal degenerations with a prevalence of 1 in 40,000 people, affecting either cones or both cones and rods simultaneously. C8ORF37 was identified as a causative gene for early onset RP and CRD. This gene encodes a protein that does not belong to any protein families or possess any domains of known functions. Several mouse lines carrying C8orf37 mutations have been generated by CRISPR/Cas9 technology in our laboratory. Phenotypic characterization of these mutant mice found disorganization of OS membrane discs and reduction of several OS membrane proteins during OS morphogenesis. Based on these observations, the central hypothesis of this study is that C8ORF37 functions in photoreceptor OS disc morphogenesis by participating in folding, degradation and/or transport of a group of OS membrane proteins in both rods and cones. To test this hypothesis, two specific aims will be conducted. In specific aim 1, the primary cause underlying the decrease of OS membrane proteins in C8orf37 knockout mice will be investigated in both rods and cones. Potential defects in protein folding, transport and/or degradation will be specifically examined. In specific aim 2, the molecular mechanism underlying C8ORF37 function will be addressed by studying the revolutionarily conserved functional domain of C8ORF37 and identifying C8ORF37-interacting proteins. Completion of this study will provide new insights into OS disc morphogenesis in photoreceptors and may benefit clinical research on RP and CRD caused by C8ORF37 mutations.