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The Journal of Neuroscience, March 10, 2004, 24(10):2516-2526; doi:10.1523/JNEUROSCI.5426-03.2004

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

Roustem Iakhine,^1 * Irit Chorna-Ornan,^2,4 * Troy Zars,¹ Natalie Elia,^3,4 Yan Cheng,¹ Zvi Selinger,^3,4 Baruch Minke,^2,4 and David R. Hyde⁵¹

¹Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, and Departments of ²Physiology and ³Biological Chemistry and ⁴Kühne Minerva Center for Studies of Visual Transduction, The Hebrew University, Jerusalem, Israel 91120

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 ninaE gene (NinaE^pp100) 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 NinaE^pp100 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 NINAE^pp100 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, NinaE^pp100 represented the first rhodopsin mutation that stabilized this protein complex. Additionally, the NinaE^pp100 mutation led to elevated levels of G_q in the cytosol, which mediated a novel retinal degeneration pathway. Eliminating both G_q and arrestin completely rescued the NinaE^pp100-dependent photoreceptor cell death, which indicated that the degeneration is entirely dependent on both G_q and arrestin. Such a combination of multiple pathological pathways resulting from a single mutation may underlie several dominant retinal diseases in humans.

Key words: Drosophila; desensitization; photoreceptor; rhodopsin; dominant degeneration; arrestin; mutant

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Received Dec 9, 2003; revised January 22, 2004; accepted January 23, 2004.

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				E. Brill, K. M. Malanson, R. A. Radu, N. V. Boukharov, Z. Wang, H.-Y. Chung, M. B. Lloyd, D. Bok, G. H. Travis, M. Obin, et al. A Novel Form of Transducin-Dependent Retinal Degeneration: Accelerated Retinal Degeneration in the Absence of Rod Transducin Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5445 - 5453. [Abstract] [Full Text] [PDF]

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