Novel Dominant Rhodopsin Mutation Triggers Two Mechanisms of Retinal Degeneration and Photoreceptor Desensitization

A variety of rod opsin mutations result in autosomal dominant retinitis pigmentosa and congenital night blindness in humans. One subset of these mutations encodes constitutively active forms of the rod opsin protein. Some of these dominant rod opsin mutant proteins, which desensitize transgenic Xenopus rods, provide an animal model for congenital night blindness. In a genetic screen to identify retinal degeneration mutants in Drosophila, we identified a dominant mutation in the ninaEgene (NinaEpp100) that encodes the rhodopsin that is expressed in photoreceptors R1-R6. Deep pseudopupil analysis and histology showed that the degeneration was attributable to a light-independent apoptosis. Whole-cell recordings revealed that the NinaEpp100 mutant photoreceptor cells were strongly desensitized, which partially masked their constitutive activity. This desensitization primarily resulted from both the persistent binding of arrestin (ARR2) to the NINAEpp100 mutant opsin and the constitutive activity of the phototransduction cascade. Whereas mutations in several Drosophila genes other than ninaE were shown to induce photoreceptor cell apoptosis by stabilizing a rhodopsin-arrestin complex, NinaEpp100 represented the first rhodopsin mutation that stabilized this protein complex. Additionally, the NinaEpp100 mutation led to elevated levels of Gqα in the cytosol, which mediated a novel retinal degeneration pathway. Eliminating both Gqα and arrestin completely rescued the NinaEpp100-dependent photoreceptor cell death, which indicated that the degeneration is entirely dependent on both Gqα and arrestin. Such a combination of multiple pathological pathways resulting from a single mutation may underlie several dominant retinal diseases in humans.

Authors: Ikhine , R. Corna-Ornan, I. Zars, T. D. Elagina, R. B. Elia, N. Cheng, Y. Selinger, Z. Minke, B. and Hyde, D. R
Year of publication: 2004
Journal: Journal of Neuroscience, 24 (10) 2516-2526

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