Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man

Abstract

Mutations in the gene encoding rhodopsin, the visual pigment in rod photoreceptors, lead to retinal degeneration in species from Drosophila to man. The pathogenic sequence from rod cell-specific mutation to degeneration of rods and cones remains unclear. To understand the disease process in man, we studied heterozygotes with 18 different rhodopsin gene mutations by using noninvasive tests of rod and cone function and retinal histopathology. Two classes of disease expression were found, and there was allele-specificity. Class A mutants lead to severely abnormal rod function across the retina early in life; topography of residual cone function parallels cone cell density. Class B mutants are compatible with normal rods in adult life in some retinal regions or throughout the retina, and there is a slow stereotypical disease sequence. Disease manifests as a loss of rod photoreceptor outer segments, not singly but in microscopic patches that coalesce into larger irregular areas of degeneration. Cone outer segment function remains normal until >75% of rod outer segments are lost. The topography of cone loss coincides with that of rod loss. Most class B mutants show an inferior-nasal to superior-temporal retinal gradient of disease vulnerability associated with visual cycle abnormalities. Class A mutant alleles behave as if cytotoxic; class B mutants can be relatively innocuous and epigenetic factors may play a major role in the retinal degeneration.

Rearrangement of the cone mosaic in the retina of the rat model of retinitis pigmentosa

“…The development of a cell line for the Rho 1D4 and the isolation of the antibody were achieved by Dr. Robert Molday and coworkers (University of British Columbia, Vancouver). Rho 1D4 antiserum recognized a band of ≈40 kDa molecular weight on western blots of rat retinal extract (Li et al,2003; Tanito et al,2007), and stained a pattern of cellular morphology in the RP rat retina that is identical with previous reports (Cideciyan et al,1998; Lee et al,2011).…”

Rearrangement of the cone mosaic in the retina of the rat model of retinitis pigmentosa

“…The development of a cell line for the Rho 1D4 and the isolation of the antibody were achieved by Dr. Robert Molday and coworkers (University of British Columbia, Vancouver). Rho 1D4 antiserum recognized a band of ≈40 kDa molecular weight on western blots of rat retinal extract (Li et al,2003; Tanito et al,2007), and stained a pattern of cellular morphology in the RP rat retina that is identical with previous reports (Cideciyan et al,1998; Lee et al,2011).…”

TheRpe65Leu450Met Variation Increases Retinal Resistance Against Light-Induced Degeneration by Slowing Rhodopsin Regeneration

“…In patients with these retinal diseases, permanent exposure to high levels of light may also be an environmental factor accelerating loss of vision (Taylor et al, 1990;Cruickshanks et al, 1993, Simons, 1993Cideciyan et al, 1998;Mata et al, 2000). This view is supported by the observation that several animal models for human retinal degeneration show a higher light damage susceptibility (LDS) than do controls (Sanyal and Hawkins, 1986;Wang et al, 1997;C.…”

Mild RPE65 -Associated Inherited Retinal Dystrophies: A Multimodal Clinical and Genetic Evaluation

“…We hypothesize that these superiorly located scotomas may arise from cumulative environmental stress, particularly light exposure. As previously described in RHO -associated disease, 29 chronic UV exposure—predominantly affecting the upper visual field—can disrupt rhodopsin regeneration, impair rod metabolism, and contribute to photoreceptor degeneration.…”

Rearrangement of the cone mosaic in the retina of the rat model of retinitis pigmentosa

“…The development of a cell line for the Rho 1D4 and the isolation of the antibody were achieved by Dr. Robert Molday and coworkers (University of British Columbia, Vancouver). Rho 1D4 antiserum recognized a band of ≈40 kDa molecular weight on western blots of rat retinal extract (Li et al,2003; Tanito et al,2007), and stained a pattern of cellular morphology in the RP rat retina that is identical with previous reports (Cideciyan et al,1998; Lee et al,2011).…”

TheRpe65Leu450Met Variation Increases Retinal Resistance Against Light-Induced Degeneration by Slowing Rhodopsin Regeneration

“…In patients with these retinal diseases, permanent exposure to high levels of light may also be an environmental factor accelerating loss of vision (Taylor et al, 1990;Cruickshanks et al, 1993, Simons, 1993Cideciyan et al, 1998;Mata et al, 2000). This view is supported by the observation that several animal models for human retinal degeneration show a higher light damage susceptibility (LDS) than do controls (Sanyal and Hawkins, 1986;Wang et al, 1997;C.…”

Mild RPE65 -Associated Inherited Retinal Dystrophies: A Multimodal Clinical and Genetic Evaluation

“…We hypothesize that these superiorly located scotomas may arise from cumulative environmental stress, particularly light exposure. As previously described in RHO -associated disease, 29 chronic UV exposure—predominantly affecting the upper visual field—can disrupt rhodopsin regeneration, impair rod metabolism, and contribute to photoreceptor degeneration.…”

Rearrangement of the cone mosaic in the retina of the rat model of retinitis pigmentosa

“…The development of a cell line for the Rho 1D4 and the isolation of the antibody were achieved by Dr. Robert Molday and coworkers (University of British Columbia, Vancouver). Rho 1D4 antiserum recognized a band of ≈40 kDa molecular weight on western blots of rat retinal extract (Li et al,2003; Tanito et al,2007), and stained a pattern of cellular morphology in the RP rat retina that is identical with previous reports (Cideciyan et al,1998; Lee et al,2011).…”

TheRpe65Leu450Met Variation Increases Retinal Resistance Against Light-Induced Degeneration by Slowing Rhodopsin Regeneration

“…In patients with these retinal diseases, permanent exposure to high levels of light may also be an environmental factor accelerating loss of vision (Taylor et al, 1990;Cruickshanks et al, 1993, Simons, 1993Cideciyan et al, 1998;Mata et al, 2000). This view is supported by the observation that several animal models for human retinal degeneration show a higher light damage susceptibility (LDS) than do controls (Sanyal and Hawkins, 1986;Wang et al, 1997;C.…”

Mild RPE65 -Associated Inherited Retinal Dystrophies: A Multimodal Clinical and Genetic Evaluation

“…We hypothesize that these superiorly located scotomas may arise from cumulative environmental stress, particularly light exposure. As previously described in RHO -associated disease, 29 chronic UV exposure—predominantly affecting the upper visual field—can disrupt rhodopsin regeneration, impair rod metabolism, and contribute to photoreceptor degeneration.…”