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  • Review Article
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Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait

Key Points

  • The major cause of adult blindness in industrialized countries is the progressive dysfunction and death of retinal photoreceptors. We discuss inherited and multifactorial forms of photoreceptor degeneration, such as retinitis pigmentosa and age-related macular degeneration, which share the common outcome of photoreceptor cell death.

  • We examine and contrast the genetic architecture of early- and late-onset forms of photoreceptor degeneration, which together represent a genetically complex trait for which there are currently 146 identified genes that influence susceptibility. The majority of these genes contain rare mutations of large effect, but some common variants also influence disease risk.

  • Many of the genes that influence photoreceptor degeneration are widely expressed, and they have been shown to affect a wide variety of cellular functions. We discuss the mode of cell death and some of the diverse disease mechanisms, which include light damage, lipid oxidation, complement activation, ciliary transport defects, endoplasmic reticulum stress, metabolic stress, mRNA splicing, survival signalling and altered bioenergetic function.

  • We argue that the photoreceptor is a uniquely vulnerable cell that is predisposed to a wide range of metabolic and other insults, consistent with the genetic heterogeneity found in photoreceptor degeneration.

  • Photoreceptor cell death has been shown to follow (stretched) exponential kinetics, consistent with a constant but increased probability of cell death specific to each genotype. This is discussed in terms of how mitochondrial retrograde and anterograde signalling pathways converge on a final common death pathway.

  • Numerous therapeutic approaches have shown some success in slowing retinal degeneration, but only one has restored vision, and to a remarkable degree. Individuals suffering from childhood-onset retinal degeneration due to retinal pigment epithelium 65 (RPE65) gene mutations treated by gene-replacement therapy showed highly significant improvements in visual function.

  • Early application of gene therapy may be crucial to avoid photoreceptor cell loss, which accounts for most visual dysfunction, as these cells cannot currently be replaced. Delayed treatment may lead to the photoreceptors becoming locked in a metabolically abnormal pro-apoptotic state, making them refractory to treatment.

  • Combined approaches, such as gene-replacement therapy together with antioxidant and/or neurotrophic support, may be necessary to slow photoreceptor cell death in situations in which substantial cell death has already occurred before treatment.

Abstract

The retina provides exquisitely sensitive vision that relies on the integrity of a uniquely vulnerable cell, the photoreceptor (PR). The genetic and mechanistic causes of retinal degeneration due to PR cell death — which occurs in conditions such as retinitis pigmentosa and age-related macular degeneration — are being successfully dissected. Over one hundred loci, some containing common variants but most containing rare variants, are implicated in the genetic architecture of this complex trait. This genetic heterogeneity results in equally diverse disease mechanisms that affect almost every aspect of PR function but converge on a common cell death pathway. Although genetic and mechanistic diversity creates challenges for therapy, some approaches — particularly gene-replacement therapy — are showing considerable promise.

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Figure 1: Structure of the human retina.
Figure 2: Functional categorization of genes that influence photoreceptor degeneration.
Figure 3: The rod photoreceptor visual cycle.
Figure 4: The photoreceptor connecting cilium.
Figure 5: Stochastic mechanisms in cell death.

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Acknowledgements

We acknowledge the support of the Macula Vision Research Foundation, Fight for Sight, the British Retinitis Pigmentosa Society and the UK Medical Research Council (A.F.W.).

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Correspondence to Alan F. Wright or Shomi S. Bhattacharya.

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Supplementary information

Supplementary Table 1

Genes involved in inherited and complex forms of photoreceptor degeneration and their proposed functional classes (PDF 326 kb)

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Glossary

Retinal pigment epithelium

A monolayer of pigmented neuroepithelial cells located between the vascular choroid and photoreceptor layer of the neural retina. It forms part of the blood–retinal barrier and has a close metabolic relationship with adjacent photoreceptors.

Outer segment

The apical extension of vertebrate photoreceptors that forms part of a modified cilium and contains densely packed membranous discs or folds containing the visual pigment and other components of the phototransduction apparatus. It is connected to the inner segment by a narrow connecting cilium.

Opsins

An evolutionarily conserved family of G-protein-coupled receptors that can function as light-sensitive photopigments when coupled to a light-sensitive chromophore, such as 11-cis retinal.

Choroid

The vascular layer of the eye lying between the retina and its fibrous scleral coat. The choroidal vasculature nourishes the outer part of the retina, including photoreceptors.

Rhodopsin

A member of the opsin family of G-protein-coupled receptors that is found in vertebrate rod photoreceptors, where it is covalently coupled to the light-sensitive chromophore 11-cis retinal to form the visual pigment.

Ciliopathy

A disorder of cilia — the small hair-like organelles that are attached to the surface of almost all polarized cells. Cilia can subserve motor or sensory functions, the latter being particularly important in photoreceptors, which contain a modified cilium.

Complement

A group of about 30 circulating proteases involved in innate immunity that are normally inactive but that can be activated by foreign or altered self antigens, initiating a cascade leading to cell lysis or phagocytosis.

Odds ratio

The odds of carrying a genetic variant (or other hazard exposure) in cases compared with controls. It can be used as a measure of effect size in case–control association studies. An odds ratio significantly different from one suggests that the genetic variant is associated with the disease or trait.

Balancing selection

Selection that favours the maintenance of more than one polymorphic allele in a population by mechanisms such as frequency-dependent selection or heterozygote advantage.

Phototransduction

The biochemical process by which a light signal is absorbed by visual pigments in photoreceptors, amplified and converted into a neuronal response.

TUNEL staining

A terminal deoxyuridine 5′-triphosphate nick-end-labelling assay. It involves the enzymatic labelling of the 3′ ends of partially degraded DNA in a cell undergoing apoptosis (and some other forms of cell death).

Apoptosis

A type of programmed cell death in which specific cellular machinery causes the cell to self-destruct. Membranous vesicles are formed and are removed by phagocytic cells.

Caspase

A family of intracellular proteases that cleave specific protein targets at cysteine-aspartic acid residues and are responsible for the breakdown of the cell during some types of (caspase-dependent) apoptotic cell death. They are synthesized as inactive procaspases that are activated by proteolytic cleavage (often by other caspases).

Autophagy

A catabolic process involving the degradation of a cell's own components by means of the lysosomal machinery.

Reactive oxygen and nitrogen species

Oxygen- or nitrogen oxide-containing free radicals that contain one or more unpaired electrons (such as superoxide or nitric oxide) together with non-radical oxygen or nitrogen oxide derivatives (such as hydrogen peroxide or peroxynitrite).

Lipofuscin

General term for a variety of coloured lipid-soluble pigments that accumulate in cells, especially during ageing.

Alternative complement pathway

A part of the innate immune system that involves a cascade of steps, starting with the binding of complement component 3b (C3b) to foreign or host cell surfaces and leading to the formation of a terminal membrane attack complex, which lyses target cells.

Microglia

Resident macrophages of haematopoietic origin located in the retina and other parts of the central nervous system. They can become motile and phagocytic after activation by specific changes in their external environment.

Inner segment

The middle part of the photoreceptor, which contains densely packed mitochondria, a basal body, a Golgi complex, endoplasmic reticulum and microtubules. It is separated from the outer segment by the connecting cilium.

Intermediary metabolism

The intermediate steps, catalysed by enzymes, in which foodstuffs are metabolized in cells and converted into cellular components.

Neurotrophic factors

(Also known as neurotrophins.) A broad group of secreted proteins that support the survival, differentiation or function of neurons.

Necrosis

Localized cell death resulting from external agents, such as injury or infection, in which there is rupture of the plasma and organellar membranes with release of the cellular contents, often leading to inflammation.

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Wright, A., Chakarova, C., Abd El-Aziz, M. et al. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet 11, 273–284 (2010). https://doi.org/10.1038/nrg2717

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