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Comparative Study
. 2006 Feb;23(4):1028-34.
doi: 10.1111/j.1460-9568.2006.04639.x.

Rpe65 as a modifier gene for inherited retinal degeneration

M Samardzija  1 , A Wenzel, M Naash, C E Remé, C Grimm
Affiliations
Comparative Study

Rpe65 as a modifier gene for inherited retinal degeneration

M Samardzija et al. Eur J Neurosci. 2006 Feb.

Abstract

Light accelerates progression of retinal degeneration in many animal models of retinitis pigmentosa (RP). A sequence variant in the Rpe65 gene (Rpe65(450Leu) or Rpe65(450Met)) can act as a modulator of light-damage susceptibility in mice by influencing the kinetics of rhodopsin regeneration and thus by modulating the photon absorption. Depending on exposure duration and light intensity applied, white fluorescent light induces photoreceptor apoptosis and retinal degeneration in wild-type mice by the activation of one of two known molecular pathways. These pathways depend, respectively, on activation of the transcription factor c-Fos/AP-1 and on phototransduction activity. Here we tested Rpe65 as a genetic modifier for inherited retinal degeneration and analysed which degenerative pathway is activated in a transgenic mouse model of autosomal dominant RP. We show that retinal degeneration was reduced in mice expressing the Rpe65(450Met) variant and that these mice retained more visual pigment rhodopsin than did transgenic mice expressing the Rpe65(450Leu) variant. In addition, lack of phototransduction slowed retinal degeneration whereas ablation of c-Fos had no effect. We conclude that sequence variations in the Rpe65 gene can act as genetic modifiers in inherited retinal degeneration, presumably by regulating the daily rate of photon absorption through the modulation of rhodopsin regeneration kinetics. Increased absorption of photons and/or light sensitivity appear to accelerate retinal degeneration via an apoptotic cascade which involves phototransduction but not c-Fos.

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Figures

Fig. 1
Fig. 1
Time course of VPP-mediated retinal degeneration was dependent on the Rpe65 sequence. (A) Retinal morphology of VPP;Rpe65450Met (left column), VPP;Rpe65450Leu (middle column) and wt;Rpe65450Leu (right column) mice at PND 11 (top row), 15 (middle row) and 18 (bottom row). Shown are representative sections of the lower temporal part of at three or more independent mice. (B) Retinal morphology of VPP;Rpe65450Met (left column), VPP;Rpe65450Leu (middle column) and Rpe65−/− (right column) mice at PND 21 (top row), 28 (second row), 42 (third row) and 56 (bottom row). The Rpe65450Leu variant accelerated the VPP-mediated retinal degeneration leading to a more pronounced thinning of the ONL and less preserved photoreceptor segments. The Rpe65 knockout only partially rescued the degeneration. Shown are representative sections of the lower temporal part of at least three independent mice. (C) Rhodopsin per retina expressed in nmol. Values are given as means + SD. Open bars, VPP;Rpe65450Met; solid bars, VPP;Rpe65450Leu. Numbers of mice are indicated. *P = 0.0046, **P < 0.0001. (D) Representative section through the lower temporal part of the retina of an Rpe65−/− mouse at PND 56. PS, photoreceptor segment; ONL, outer nuclear layer; INL, inner nuclear layer.
Fig. 2
Fig. 2
Dark rearing partially rescued retinal degeneration in VPP;RPE65450Leu mice. (A) Representative sections of the lower temporal retina of mice reared in cyclic light (left) or reared in darkness (right) for 42 days. Mice were of the Rpe65450Leu genotype. (B) Rhodopsin per retina [nmol] in VPP;Rpe65450Leu and VPP;RPE65450Met mice reared in cyclic light and in dark-reared VPP;Rpe65450Leu mice as indicated. Values are given as means + SD. Numbers of retinas are indicated. *P = 0.0164. Rhodopsin values in dark-reared VPP;Rpe65450Leu mice were not significantly different (P = 0.304) from rhodopsin values in cyclic-reared VPP;RPE65450Met mice.
Fig. 3
Fig. 3
VPP-mediated retinal degeneration was independent of c-Fos. (A) c-fos gene expression in retinas isolated from wt or VPP mice at the PNDs indicated. Total RNA from three retinas of three mice were pooled for RT-PCR analysis at each timepoint; M, 100-bp DNA marker. (B) Representative sections of the lower temporal retina of PND 28 VPP or VPP;c-fos−/− mice as indicated. All mice were of the Rpe65450Met genotype. (C) Rhodopsin per retina expressed in nmol. Values are given as means + SD. Numbers of retinas are indicated. *P < 0.0001.
Fig. 4
Fig. 4
VPP-mediated retinal degeneration was influenced by phototransduction. (A) Representative sections of the lower temporal retina of VPP and of VPP;Gnat−/− mice raised in cyclic light. Lack of functional rod transducin improved retinal morphology in VPP;Rpe65450Leu mice: an increased number of photoreceptor nuclei in the ONL is apparent and photoreceptor segments are better preserved. All mice were of the Rpe65450Leu genotype and were taken at the PNDs indicated. (B) Rhodopsin per retina expressed in nmol. Values are given as means + SD. Solid bars, VPP;Rpe65450Leu; open bars, VPP;Gnat-1−/−;Rpe65450Met. Numbers of retinas are indicated. *P = 0.0166, **P = 0.0053. Abbreviations as in Fig. 1.
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