Retinitis Pigmentosa: Defined From a Molecular Point of View

doi:10.1016/S0039-6257(98)00046-0

Survey of Ophthalmology

Volume 43, Issue 4, January–February 1999, Pages 321-334

https://doi.org/10.1016/S0039-6257(98)00046-0 Get rights and content

Abstract

Retinitis pigmentosa (RP) denotes a group of hereditary retinal dystrophies, characterized by the early onset of night blindness followed by a progressive loss of the visual field. The primary defect underlying RP affects the function of the rod photoreceptor cell, and, subsequently, mostly unknown molecular and cellular mechanisms trigger the apoptotic degeneration of these photoreceptor cells. Retinitis pigmentosa is very heterogeneous, both phenotypically and genetically. In this review we propose a tentative classification of RP based on the functional systems affected by the mutated proteins. This classification connects the variety of phenotypes to the mutations and segregation patterns observed in RP. Current progress in the identification of the molecular defects underlying RP reveals that at least three distinct functional mechanisms may be affected: 1) the daily renewal and shedding of the photoreceptor outer segments, 2) the visual transduction cascade, and 3) the retinol (vitamin A) metabolism. The first group includes the rhodopsin and peripherin/RDS genes, and mutations in these genes often result in a dominant phenotype. The second group is predominantly associated with a recessive phenotype that results, as we argue, from continuous inactivation of the transduction pathway. Disturbances in the retinal metabolism seem to be associated with equal rod and cone involvement and the presence of deposits in the retinal pigment epithelium.

Section snippets

The photoreceptor outer segment

Vision is mediated by the photoreceptor cells in the retina, where rod and cone photoreceptors can be distinguished. Rods represent 97% of all photoreceptors and mediate vision in dim light. Cones are the mediators of detailed vision and color vision, and their density increases toward the center of the retina, the macula. The primary defect in RP usually disrupts vision in dim light, resulting in night blindness. Different aspects of rod function will be described here.

A rod contains an outer

Mutations affecting renewal and shedding of the rod outer segment

With its specialized structure and function, the photoreceptor outer segment is a crucial compound in the processes mediating vision. The daily renewal and shedding of outer segment disks is a delicate process that forms a metabolic burden to the photoreceptor and RPE cells. Disruption of the continuous disk renewal or overactive degradation may lead to shortened and malfunctioning outer segments. Deficient degradation of the shedded disk material will result in the formation of retinal

Method of Literature Search

Literature search was performed using MEDLINE, predominantly on the databases of the last 10 years. Search topics used were retinitis pigmentosa, and specified on gene, phototransduction pathway, and mutations. Detailed data were retrieved by searches on the specific gene or protein of interest. An overview of all loci and genes presently known to be involved in ocular disease is available at http://utsph. sph.uth.tmc.edu/www/utsph/RetNet/home.htm

Glossary of terms used

Chromophore: the light-absorbing group in the visual system, being 11-cis-retinal in human rods.

Cone/cone-rod dystrophy: retinal dystrophy that is characterized by either a predominant involvement of cones (cone dystrophy) or the equal involvement of cones and rods (cone-rod dystrophy).

Codon: a unit of three nucleotides that code for a single amino acid of a protein.

Compound heterozygote: the presence of two different mutations in a single gene in an affected individual. One of both mutations

Outline

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Acknowledgements

S. van Soest was supported by a grant from The Netherlands Society for Scientific Research (NWO).

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Citation Excerpt :
Inherited retinal degenerations are a common cause of visual impairment, including blindness (prevalence 1:2000) (Sohocki et al., 2001). An amino acid substitution (P23H) in rhodopsin, the light-sensing G-protein-coupled receptor of rod photoreceptors, accounts for 4.8% of inherited retinal degeneration cases in the USA (Daiger et al., 2019; Dryja et al., 1990; Sohocki et al., 2001; Van Soest et al., 1999). In patients and animal models with this mutation, rods progressively degenerate (e.g., rod loss in mice: 20% at 1 month, 60% at 3 months, 73% at 5 months) (Aleman et al., 2008; Bonilha et al., 2015; Leinonen et al., 2020; Machida et al., 2000; Ross et al., 2012; Sakami et al., 2011; Steinberg et al., 1996).
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Retinitis pigmentosa (RP) is a group of genetically heterogeneous retinal diseases with more than 80 identified causative genes to date. Mutations in the RHO (rhodopsin, OMIM, 180380) are the most common cause of autosomal dominant RP (adRP) worldwide. RHO is also one of the few RP genes that can cause autosomal recessive RP (arRP). To explore the frequency of RP mutations in Chinese populations, panel-based NGS (next-generation sequencing) screening and Sanger sequencing validation were performed for RP patients from 72 unrelated Chinese families. Here we reported the identified mutations only in the RHO gene. Our results showed that 4 mutations in RHO were detected in 5 (6.94%) of the 72 RP families, including two known missense mutations, c.158C > G (p.P53R) and c.551A > C (p.Q184P), and two novel mutations, c.34delC (p.P12NA) and c.82C > T (p.Q28X). The c.34delC (p.P12NA) mutation was detected in heterozygous state in one patient with intermediate RP phenotype. The c.82C > T (p.Q28X) mutation was found in a homozygous state in one proband with advanced RP phenotype at the age of 32. Clinical examination of the heterozygous carriers of c.82C > T (p.Q28X) in that family showed that the father at the age of 60s experienced no symptoms of RP and normal fundus examinations but displayed reduced electroretinography (ERG) and abnormal visual field. The sister and brother at the age of 30s showed no typical aspects of RP phenotypes. Our results not only expand the mutation spectrum of the RHO gene, but also suggest that the 2 null mutations might play minor dominant effects, leading to less severe and slower retinal degeneration in heterozygous state and more severe phenotype in homozygous state.
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To evaluate yearly progression of retinitis pigmentosa (RP) using microperimetry (MP) performed on Nidek MP1 (NAVIS Software v1.7; Nidek Technologies, Padova, Italy).
Retrospective longitudinal study.
RP patients with consecutive MP tests (using the same test settings).
Data were collected as part of the Photoreceptor Cell Death in Retinitis Pigmentosa Retrospective (PREP-1) study. Visual acuity, fixation stability, mean sensitivity, and regional sensitivity were assessed at baseline and at yearly follow-up appointments. Regional sensitivity was calculated based on 2 methods. Method 1 involved topographical division into central macula (CM) and paracentral macula (PM). Method 2 involved functional division into the edge of scotoma (ES) and the seeing retina (SR). Linear mixed-effects models were used to assess the annual rate of change for each parameter, adjusted for disease duration.
Annual rate of change of visual acuity, fixation stability, and retinal sensitivities (mean sensitivity and regional sensitivities using methods 1 and 2).
In total, 75 eyes of 39 patients (median age, 56 y; males, 57%) with a follow-up period ranging from 1 to 4 years were reviewed. Visual acuity at baseline was positively correlated with all retinal sensitivity parameters, most strongly with CM sensitivity (r = 0.545, P < 0.001). There was no change in visual acuity (P = 0.075) or fixation stability (P = 0.371) per year. All retinal sensitivity parameters had a significant decline per year (P < 0.001), with a decline of 0.4 decibel (dB) for mean sensitivity, 0.6 dB for CM, 0.3 dB for PM, 1.3 dB for ES, and 1.1 dB for SR. Method 2 identified the greatest number of cases, with a significant decline in regional sensitivity.
MP can detect significant changes in regional sensitivity over a 1-year period in patients with RP, even as visual acuity and fixation remain stable. An individualized approach to analyzing retinal sensitivity derived from MP may offer a useful outcome measure for future clinical trials.
Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives
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Retinitis Pigmentosa (RP) is a hereditary retinopathy that affects about 2.5 million people worldwide. It is characterized with progressive loss of rods and cones and causes severe visual dysfunction and eventual blindness in bilateral eyes. In addition to more than 3000 genetic mutations from about 70 genes, a wide genetic overlap with other types of retinal dystrophies has been reported with RP. This diversity of genetic pathophysiology makes treatment extremely challenging. Although therapeutic attempts have been made using various pharmacologic agents (neurotrophic factors, antioxidants, and anti-apoptotic agents), most are not targeted to the fundamental cause of RP, and their clinical efficacy has not been clearly proven. Current therapies for RP in ongoing or completed clinical trials include gene therapy, cell therapy, and retinal prostheses. Gene therapy, a strategy to correct the genetic defects using viral or non-viral vectors, has the potential to achieve definitive treatment by replacing or silencing a causative gene. Among many clinical trials of gene therapy for hereditary retinal diseases, a phase 3 clinical trial of voretigene neparvovec (AAV2-hRPE65v2, Luxturna) recently showed significant efficacy for RPE65-mediated inherited retinal dystrophy including Leber congenital amaurosis and RP. It is about to be approved as the first ocular gene therapy biologic product. Despite current limitations such as limited target genes and indicated patients, modest efficacy, and the invasive administration method, development in gene editing technology and novel gene delivery carriers make gene therapy a promising therapeutic modality for RP and other hereditary retinal dystrophies in the future.

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ArticlesRetinitis Pigmentosa: Defined From a Molecular Point of View

Abstract

Section snippets

The photoreceptor outer segment

Mutations affecting renewal and shedding of the rod outer segment

Method of Literature Search

Glossary of terms used

Outline

Acknowledgements

FEBS Lett

J Biol Chem

Am J Ophthalmol

Genomics

J Biol Chem

J Biol Chem

Genomics

Exp Eye Res

Exp Eye Res

Ophthalmology

Am J Hum Genet

J Biol Chem

Genomics

Exp Eye Res

J Biol Chem

Cell

Am J Ophthalmol

Genomics

Genomics

A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy

Nat Genet

Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration

Science

Identification of a sixth locus for autosomal dominant retinitis pigmentosa on chromosome 19

Hum Mol Genet

Evidence for a major retinitis pigmentosa locus on 19q13.4 (RP11), and association with a unique bimodal expressivity phenotype

Am J Hum Genet

Phenotypes in three Swedish families with X-linked retinitis pigmentosa caused by different mutations in the RPGR gene

Am J Ophthalmol

Extensive intrafamilial and interfamilial phenotypic variation among patients with autosomal dominant retinal dystrophy and mutations in the human RDS/peripherin gene

Br J Ophthalmol

TULP1 mutation in two extended Dominican kindreds with autosomal recessive retinitis pigmentosa

Nat Genet

Localization of the photoreceptor gene ROM1 to human chromosome 11 and mouse chromosome 19sublocalization to human 11q13 between PGA and PYGM

Am J Hum Genet

Cloning of the cDNA for a novel photoreceptor protein (rom-1) identifies a disk rim protein family implicated in human retinopathies

Neuron

Mutation analysis of the ROM1 gene in retinitis pigmentosa

Hum Mol Genet

An eight locus for autosomal dominant retinitis pigmentosa is linked to chromosome 17q

Hum Mol Genet

Evidence against the involvement of recoverin in autosomal recessive retinitis pigmentosa in 42 Spanish families

Hum Genet

How photons start vision

Proc Natl Acad Sci USA

Close genetic linkage between X-linked retinitis pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA probe L1.28

Nature

Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1

Nature

Processing and transport of retinoids by the retinal pigment epithelium

Eye

Retinal degeneration in the rd mouse is caused by a defect in the β subunit of rod cGMP-phosphodiesterase

Nature

Hereditary pigmentary degeneration of the retina

A new subunit of the cyclic nucleotide-gated cation channel in retinal rods

Proc Natl Acad Sci USA

Some cytological and initial biochemical observations on photoreceptors in retinas of rds mice

Invest Ophthalmol Vis Sci

Molecular cloning, primary structure and orientation of the vertebrate photoreceptor cell protein peripherin in the rod outer segment disc membrane

Biochemistry

Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice mutations in the Stargardt’s disease

ABCR. Hum Mol Genet

Human rod photoreceptor cGMP-gated channelamino acid sequence, gene structure, and functional expression

J Neurosci

A point mutation in the rhodopsin gene in one form of retinitis pigmentosa

Nature

Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness

Nat Genet

Mutation in the gene encoding the α-subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa

Proc Natl Acad Sci USA

Molecular genetics of retinitis pigmentosa

Articles
Retinitis Pigmentosa: Defined From a Molecular Point of View