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Elliott Brill, Katherine M. Malanson, Roxana A. Radu, Natalia V. Boukharov, Zhongyan Wang, Hae-Yun Chung, Marcia B. Lloyd, Dean Bok, Gabriel H. Travis, Martin Obin, Janis Lem; A Novel Form of Transducin-Dependent Retinal Degeneration: Accelerated Retinal Degeneration in the Absence of Rod Transducin. Invest. Ophthalmol. Vis. Sci. 2007;48(12):5445-5453. doi: 10.1167/iovs.06-1402.
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purpose. Rhodopsin mutations account for approximately 25% of human autosomal dominant retinal degenerations. However, the molecular mechanisms by which rhodopsin mutations cause photoreceptor cell death are unclear. Mutations in genes involved in the termination of rhodopsin signaling activity have been shown to cause degeneration by persistent activation of the phototransduction cascade. This study examined whether three disease-associated rhodopsin substitutions Pro347Ser, Lys296Glu, and the triple mutant Val20Gly, Pro23His, Pro27Leu (VPP) caused degeneration by persistent transducin-mediated signaling activity.
methods. Transgenic mice expressing each of the rhodopsin mutants were crossed onto a transducin α-subunit null (Tr α − / −) background, and the rates of photoreceptor degeneration were compared with those of transgenic mice on a wild-type background.
results. Mice expressing VPP-substituted rhodopsin had the same severity of degeneration in the presence or absence of Trα. Unexpectedly, mice expressing Pro347Ser- or Lys296Glu-substituted rhodopsins exhibited faster degeneration on a Tr α − / − background. To test whether the absence of α-transducin contributed to degeneration by favoring the formation of stable rhodopsin/arrestin complexes, mutant Pro347Ser +, Tr α − / − mice lacking arrestin (Arr − / −) were analyzed. Rhodopsin/arrestin complexes were found not to contribute to degeneration.
conclusions. The authors hypothesized that the decay of metarhodopsin to apo-opsin and free all-trans-retinaldehyde is faster with Pro347Ser-substituted rhodopsin than it is with wild-type rhodopsin. Consistent with this, the lipofuscin fluorophores A2PE, A2E, and A2PE-H2, which form from retinaldehyde, were elevated in Pro347Ser transgenic mice.
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