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. 1998 Jun 9;95(12):7103-8.
doi: 10.1073/pnas.95.12.7103.

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

A V Cideciyan  1 , D C Hood, Y Huang, E Banin, Z Y Li, E M Stone, A H Milam, S G Jacobson
Affiliations
Free PMC article

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

A V Cideciyan et al. Proc Natl Acad Sci U S A. .
Free PMC article

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.

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Figures

Figure 1
Figure 1
Rod and cone photoreceptor physiology. (A) ERG photoresponses (thin lines) in a representative normal and two patients evoked by one red (middle) and two blue (top and bottom) flash stimuli. Waveforms are fitted with the phototransduction model (thick line) that is the sum of rod (dashed lines) and cone (dotted lines) components. (B) Summary of rod and cone photoresponse data in 13 patients; dashed lines are lower limits (mean − 2 SD) of normal. (C) ROS membrane area estimated (% of normal) by adjusting rod photoresponse amplitudes shown in B for scotomatous retinal regions by kinetic perimetry (target V-4e).
Figure 2
Figure 2
Relationship between rod and cone function measured psychophysically. (A) Maps of RSL and CSL across the visual field of four patients displayed on a gray scale. All maps are displayed as right eyes: superior (S), inferior (I), nasal (N), and temporal (T) fields. White is normal; black is >3 l.u. of sensitivity loss for rods, unmeasurable for cones; physiological blindspot is shown as black at 12°T. Representative loci are marked with no RSL or CSL (I); RSL but no CSL (II); and combined RSL and CSL (III). (B) Mean CSL as a function of RSL (•); error bars are ± 1 SEM. The loci marked in A are shown with gray symbols. Arrowheads against axes denote lower limits of normal (mean − 2 SD) averaged across the visual field. Gray line is the linear regression applied to the data in the range from 1.6 through 3.5 l.u. of RSL. (Inset) Three subsets of the patient population: Class A (n = 12, □); Class B1 (n = 29, ○) and B2 (n = 16, ▵).
Figure 3
Figure 3
Topographical variation of rod and cone dysfunction. (A) Maps of RSL and CSL in two class A patients, V345L and R135L, displayed in Fig. 2A. (B) Summary contour map of CSL in eight class A patients displaying 50th percentile contours of selected sensitivity losses; the loss in l.u. for each contour shown on the color scale (Sc, scotoma); isoeccentricity lines are 20, 40, and 60°. Maps are shown as a visual field of the right eye. (C) Histogram of the maximum intraretinal variation of RSL in 28 class B patients with relatively mild dysfunction (<1.5 l.u. of RSL in some retinal regions). (D) Summary contour maps of RSL and CSL for 16 class B patients showing >3 l.u. of intraretinal RSL variation. (E) Maps of RSL and CSL in three family members with the G106R mutation having increasing (left to right) degrees of disease severity (displayed as in Fig. 2A). (F) Dark adaptation kinetics of class B disease, representing nine mutations. Each symbol is the time to recover to within 0.5 l.u. of prebleach sensitivity after a 99% bleach; results of two to three least affected patients of each mutation are averaged. Gray lines show the normal limits.
Figure 4
Figure 4
Evidence for microscopic patches of photoreceptor disease. (A) Rod ERG b-wave maximum amplitude plotted against rod photoresponse maximum amplitude; both measures are shown as fraction of mean normal. Line represents equal reduction of the two variables. (B) Computational model of rod bipolar output as a function of ROS area shown as fractions of normal; curves are labeled by the size of the dysfunctional patches used in the simulations, error bars are ± 2 SD (C-H) Flat mount preparations of the superior regions of human retinas. ROS have been immunolabeled with anti-rhodopsin (green), and COS have been labeled with anti-red/green cone opsin (red). Calibration bars indicate 10 μm in C-F and H and 20 μm in G. (C) Periphery of normal human retina. (D) Far periphery (3 mm from ora serrata) of G106R retina showing near normal ROS and COS. (E) Periphery (5 mm from ora serrata) of T17M retina showing shortening of ROS and COS and presence of small gaps (arrows) in the layer of ROS. (F) Periphery (10 mm from ora serrata) of T17M retina showing a larger patch of ROS loss; retained COS are short. (G) Low magnification of G106R mid-periphery with larger patches that contain no ROS. (H) High magnification of a region in G. Within a rod-free patch, only cone somata (arrowheads) are retained. Their surface membrane are cone opsin positive. Short ROS and COS are present near the edge of the rod-free patch.
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