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Retinitis pigmentosa (RP) is a common genetic eye disease affecting about 1 in 3500 people worldwide with pan-ethnic occurrence. So far there is no effective treatment for RP. This paper gives an overview on recent advances in molecular genetics of RP with emphasis on the important gene mutations for diagnosis and prognosis, and a review on gene therapy of RP.
Retinitis pigmentosa (RP) affects 1 in 3,000 individuals worldwide, with 30%-40% of cases inherited as autosomal dominant (AD). Mutations in RHO (RP4) are the most common cause of ADRP. Because most RHO mutations exert gain-of-function or dominant-negative effects, conventional gene supplementation is insufficient, requiring mutant allele inactivation. Allele-specific editing is impractical, as each mutation requires a unique therapeutic strategy. We present a mutation-agnostic, RHO-specific approach using adeno-associated viral vector-mediated homology-independent targeted integration (AAV-HITI). Optimized donor DNA design enables targeted integration and efficient transgene expression from the endogenous RHO locus. In a humanized RP4 mouse model harboring the RHO P23H mutant allele alongside an endogenous wild-type mouse Rho allele, AAV-HITI significantly improves retinal structure, function, and visual acuity up to 1 year post-treatment. Comprehensive molecular analyses characterize on-target editing in mouse retina and off-target editing in a human cell line. These findings establish an effective, human-centric AAV-HITI platform for RP4 and support its evaluation in this and other dominant genetic conditions.
Retinitis pigmentosa (RP) is the most common hereditary dystrophic disease of the retina. About 10% of the affected families show the X-linked trait. The close link observed between the gene locus (RP2) and a polymorphic DNA marker (DXS7) on the proximal short arm of the X-chromosome permits an indirect genotype diagnosis and can be helpful in carrier detection and genetic counseling. A case is presented in which the carrier risk of a female consultant dropped from 50% a priori to less than 2% by the use of clinical findings and DNA analysis.
Retinitis pigmentosa (RP) is a genetically heterogeneous disease and an important cause of blindness in the state of Andhra Pradesh in India. In an attempt to identify the disease locus in families with the recessive form of the disease, we used the approach of screening for homozygosity by descent in offspring of consanguineous and nonconsanguineous families with RP. Microsatellite markers closely flanking 21 known candidate genes for RP were genotyped in parents and affected offspring to determine whether there was homozygosity at these loci that was shared by affected individuals of a family. This screening approach may be a rapid preliminary method to test known loci for possible cosegregation with disease.
Retinitis pigmentosa (RP) is one of the most genetically heterogeneous inherited disorders. Twelve genes have now been identified in the autosomal dominant form of the disease, including some recently characterized genes that show unprecedented and fascinating traits in both their function and in their expression profiles. These include many widely expressed genes encoding components of the spliceosome and a guanine nucleotide synthesis gene. Intriguingly, the most recently identified dominant gene does not appear to be expressed in the neuronal retina but is expressed in the capillaries of the choroid. In attempting to understand the effects of mutations in these genes, investigators are forced to re-evaluate their thinking on the molecular mechanisms of genetic blindness and to undertake an increasingly inter-disciplinary approach in their analysis of this disease. Recently, this has resulted in significant developments in the elucidation of the molecular pathogenesis of RP.
Retinitis pigmentosa is an inherited progressive disease which is a major cause of blindness in western communities. It can be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive disorder. In the autosomal dominant form (adRP), which comprises about 25% of total cases, approximately 30% of families have mutations in the gene encoding the rod photoreceptor-specific protein rhodopsin. This is the transmembrane protein which, when photoexcited, initiates the visual transduction cascade. So far, 41 single-base-pair (bp) substitutions, one two-bp substitution, and four deletions ranging from 3 to 42 bp have been identified in this gene. These mutations do not appear to be significantly clustered in a specific part of the protein, but occur in all three major domains, namely the intradiscal, transmembrane, and cytoplasmic regions. Different mutations appear to cause differences in the severity of the disease, though there is considerable variability in severity even within the same family, at least in certain of these mutations. Identification of all the mutations involved in rhodopsin-RP should allow accurate and early detection of affected individuals, informed genetic counselling, as well as furthering our knowledge of the disease process involved.
Retinitis pigmentosa (RP) is a prevalent cause of blindness caused by a large number of different mutations in many different genes. The mutations result in rod photoreceptor cell death, but it is unknown why cones die. In this study, we tested the hypothesis that cones die from oxidative damage by performing immunohistochemical staining for biomarkers of oxidative damage in a transgenic pig model of RP. The presence of acrolein- and 4-hydroxynonenal-adducts on proteins is a specific indicator that lipid peroxidation has occurred, and there was strong immunofluorescent staining for both in cone inner segments (IS) of two 10-month-old transgenic pigs in which almost all rods had died, compared to faint staining in two 10-month-old control pig retinas. In 22- and 24-month-old transgenic pigs in which all rods and many cones had died, staining was strong in cone axons and some cell bodies as well as IS indicating progression in oxidative damage between 10 and 22 months. Biomarkers for oxidative damage to proteins and DNA also showed progressive oxidative damage to those macromolecules in cones during the course of RP. These data support the hypothesis that the death of rods results in decreased oxygen consumption and hyperoxia in the outer retina resulting in gradual cone cell death from oxidative damage. This hypothesis has important therapeutic implications and deserves rapid evaluation.
Retinitis pigmentosa (RP) is a label for a group of diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cones. The mechanism of cone cell death is uncertain. Rods are a major source of oxygen utilization in the retina and, after rods die, the level of oxygen in the outer retina is increased. In this study, we used the rd1 mouse model of RP to test the hypothesis that cones die from oxidative damage. A mixture of antioxidants was selected to try to maximize protection against oxidative damage achievable by exogenous supplements; alpha-tocopherol (200 mg/kg), ascorbic acid (250 mg/kg), Mn(III)tetrakis (4-benzoic acid) porphyrin (10 mg/kg), and alpha-lipoic acid (100 mg/kg). Mice were treated with daily injections of the mixture or each component alone between postnatal day (P)18 and P35. Between P18 and P35, there was an increase in two biomarkers of oxidative damage, carbonyl adducts measured by ELISA and immunohistochemical staining for acrolein, in the retinas of rd1 mice. The staining for acrolein in remaining cones at P35 was eliminated in antioxidant-treated rd1 mice, confirming that the treatment markedly reduced oxidative damage in cones; this was accompanied by a 2-fold increase in cone cell density and a 50% increase in medium-wavelength cone opsin mRNA. Antioxidants also caused some preservation of cone function based upon photopic electroretinograms. These data support the hypothesis that gradual cone cell death after rod cell death in RP is due to oxidative damage, and that antioxidant therapy may provide benefit.
A 21-year-old white man with retinitis pigmentosa was found to have an isolated patch of retinal neovascularization. Ocular and systemic evaluation failed to reveal a recognized cause for the neovascularization. This case is felt to represent the unusual association of retinitis pigmentosa and retinal neovascularization.
Four patients with retinitis pigmentosa and either disc or peripheral retinal neovascularization with recurrent vitreous hemorrhage are described. One patient with peripheral retinal neovascularization also had rubeosis and neovascular glaucoma. The effects of relative hyperoxia on the retinal microcirculation in retinitis pigmentosa as well as intraocular inflammation may account for such changes. Laser photocoagulation appears effective in preventing vitreous hemorrhage in these patients, but systemic administration of corticosteroids did not cause the new vessels to regress.
Twenty-five patients with retinitis pigmentosa and retinal leakage were investigated. Oedema was present in dominant and X-linked inherited disease and is likely to be present in recessive disease as well. We suggest that this might be a general response seen in many types of tapeto-retinal degeneration to actively degenerating photoreceptors or pigment epithelium.
Recent biochemical findings in the human disease, retinitis pigmentosa, and related retinal degenerative diseases in animals were reviewed and discussed. While the biochemical etiology of the human disease is not known, there are indications that retinal degeneration in the rd mouse and the Irish Setter dog are related to a deficiency in cGMP phosphodiesterase and the accumulation of cGMP in the photoreceptor outer segments. The biochemical basis of retinal degeneration in the Royal College of Surgeons (RCS) rat does not seem to be related to a defect in the metabolism of cGMP, but there are suggestions that a defect in retinoid metabolism may be involved. The possibility that the defect in RCS rats may involve receptors on the membranes of the cells of the retinal pigment epithelium or phagocytic markers on those of the rod outer segment disks was discussed.
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Retinitis pigmentosa (RP) is a group of genetically heterogeneous diseases with autosomal recessive (AR), autosomal dominant, and X-linked modes of inheritance. Autosomal recessive retinitis pigmentosa (ARRP) is the most common form in Japan. A genetic analysis was done to determine the prevalence of ARRP indirectly, to provide an estimation of changing trends in the overall prevalence of RP. Data on the frequency of consanguinity and marriage year of normal parents of 59 ARRP patients were obtained from a nationwide multicenter survey of typical retinitis pigmentosa conducted in 1990. The gene frequency of ARRP was 0.01145 (Dahlberg's formula). In 1990, the number of young symptomatic ARRP patients decreased, while the number of patients aged 40 years and older increased. The total number of symptomatic ARRP patients in 1990 was nearly 21% higher than in 1970. Despite a dramatic decline in consanguinity in recent decades in Japan, the number of ARRP patients has increased. This increase is attributed to greater longevity and overall population growth. Our results suggest that the total number of RP patients has not decreased, and may even have increased.
The family of inherited ocular diseases that is collectively known as retinitis pigmentosa is a major cause of progressive retinal disease worldwide. As such, this family of diseases has been the object of much scientific scrutiny, both clinical and basic. The recent application of molecular genetic analyses has heralded the rapid elucidation of the underlying gene defects in many cases. In this article, the fundamental clinical and electroretinographic characteristics of retinitis pigmentosa will be recalled. Additionally, the current understanding of the genetic causes of retinitis pigmentosa will be reviewed, and the identified causative genes will be classified into groups related by function.
Patients with retinitis pigmentosa, other retinal degenerations and a group of normal volunteers were included in a masked study designed to examine the existence of autoimmune reactions toward retinal antigens and the possible defect in lymphokine production (IL-1, IL-2 and gamma interferon). The results obtained did not show any specific anamnestic response to the retinal S-Ag nor any outstanding defect in gamma interferon production by the lymphocytes of patients with retinitis pigmentosa. It is suggested that a larger masked study be conducted as soon as possible in order to clarify these aspects of immune aberrations in patients with retinitis pigmentosa.
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