Polygenic disease and retinitis pigmentosa: albinism exacerbates photoreceptor degeneration induced by the expression of a mutant opsin in transgenic mice

Abstract

Expression of a mouse opsin transgene containing three point mutations (V20G, P23H, and P27L; termed VPP) causes a progressive photoreceptor degeneration that resembles in many important respects that seen in patients with autosomal dominant retinitis pigmentosa caused by a P23H point mutation. We have attempted to determine whether the degree of degeneration induced by expression of the transgene is influenced by albinism, a genetically mediated recessive trait that results in a deficiency in melanin formation in pigmented tissues throughout the body. Litters of albino and pigmented mice (normal as well as transgenic) were reared in either darkness or cyclic light. Retinal structure and function were evaluated by light microscopy, electroretinography (ERG), and retinal densitometry. The data were consistent in demonstrating that at similar ages, the extent of photoreceptor degeneration was greater in transgenic albino animals than in their pigmented counterparts. The albino VPP mice had significantly fewer cell bodies in the outer nuclear layer of the retina, a larger reduction in ERG amplitude, and a lower rhodopsin content in the rod photoreceptors. These structural and functional differences could not be attributed to the greater level of retinal illumination experienced by the albino retina under normal ambient conditions, because they persisted when pigmented and albino mice were reared in darkness from birth. Although the explanation remains unclear, our findings indicate that the rate of photoreceptor degeneration in VPP mice is adversely affected by the existence of the albino phenotype, a factor that may have implications for the counseling of human patients with retinitis pigmentosa and a familial history of other genetic disorders.

Fig. 1.

Representative histological sections of retinas from normal and transgenic mice. A, B, Sections taken from normal albino mice reared in cyclic light (A) or darkness (B). No differences were observed between normal albino and pigmented animals regardless of light conditions. The remaining sections were taken from VPP mice that were either albino (C, D) or pigmented (E, F). Under both lighting conditions, the thickness of the ONL was greater in the retinas of pigmented transgenic mice. Scale bar, 20 μm.Brackets indicate the extent of the ONL.

Fig. 2.

Number of photoreceptor nuclei counted within a 70 μm microscopic field that was centered at 300 μm from the edge of the optic nerve head. All values are expressed as a percentage of the values obtained from normal littermates; each bar represents the mean (± SEM) of three to six measurements. Both the thickness and the cellular content of the ONL were significantly greater in pigmented than in albino VPP mice (all p < 0.05).

Fig. 3.

A, Electroretinograms obtained in response to a high intensity strobe flash (0.85 log cd sec/m²) presented to the dark-adapted eye from normal mice (top traces) and VPP mice (bottom traces). B, Amplitude of the ERG a-wave. All values are expressed as a percentage of the values obtained from normal littermates; each bar represents the mean ± SEM of 15–23 measurements. Responses were significantly greater in pigmented than in albino VPP mice (all p < 0.001).

Fig. 4.

Rhodopsin density difference spectra obtained from albino and pigmented VPP mice. Mice were reared under cyclic light (A) or in complete darkness (B). Each set of data is plotted as a percentage of the values obtained from normal littermates and represents the mean of 10–13 measurements; thedashed lines indicate the normal difference spectrum. For both lighting conditions, the rhodopsin content of the pigmented VPP retina was significantly greater than in albino VPP mice (allp < 0.001).