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At least 19 recordsLinked to original sources
PubMed1992

Calcium channel blockers inhibit retinal degeneration in the retinal-degeneration-B mutant of Drosophila.

Light accelerates degeneration of photoreceptor cells of the retinal degeneration B (rdgB) mutant of Drosophila. During early stages of degeneration, light stimuli evoke spikes from photoreceptors of the mutant fly; no spikes can be recorded from photoreceptors of the wild-type fly. Production of spike potentials from mutant photoreceptors was blocked by diltiazem, verapamil hydrochloride, and cadmium. Little, if any, effect of the (-)-cis isomer or (+)-cis isomer of diltiazem on the light response was seen. Further, the (+)-cis isomer was approximately 50 times more effective than the (-)-cis isomer in blocking the Ca2+ spikes, indicating that diltiazem action on the rdgB eye is mediated by means of blocking voltage-sensitive Ca2+ channels, rather than by blocking the light-sensitive channels. Application of the Ca(2+)-channel blockers (+)-cis-diltiazem and verapamil hydrochloride to the eyes of rdgB flies over a 7-day period largely inhibited light-dependent degeneration of the photoreceptor cells. Pulse labeling with [32P]phosphate showed much greater incorporation into eye proteins of [32P]phosphate in rdgB flies than in wild-type flies. Retarding the light-induced photoreceptor degeneration in the mutant by Ca(2+)-channel blockers, thus, suggests that toxic increase in intracellular Ca2+ by means of voltage-gated Ca2+ channels, possibly secondary to excessive phosphorylation, leads to photoreceptor degeneration in the rdgB mutant.

Action Potentials↗
PubMed2025

Novel photoreceptor-specific promoters for gene therapy in mid- to late-stage retinal degeneration.

Inherited retinal degenerations (IRDs) cause progressive photoreceptor loss, leading to vision impairment. Gene therapy using adeno-associated viral (AAV) vectors holds immense promise for treating these conditions. However, achieving optimal gene expression at mid to late stages of retinal degeneration remains challenging due to scarcity of efficient photoreceptor-specific promoters expressed at these disease stages. This study aimed to identify and validate novel promoters capable of robust and specific transgene expression when ≥50% of photoreceptors are lost. Analysis of transcriptomic data from two naturally occurring canine IRD models, laser capture microdissection of retinal cryosections followed by qPCR, and RNA in situ hybridization identified six promising genes with sustained or upregulated expression in photoreceptors in late-stage disease. Upstream cis-regulatory elements of both canine and human orthologs were identified and characterized using in silico analyses and dual-luciferase assays. Short promoters (≤840 base pairs) derived from GNGT2, IMPG2, and PDE6H genes exhibited robust reporter gene expression in photoreceptors when delivered via AAV to the subretinal space of two non-allelic canine IRD models at mid and late disease stages. These findings provide a strategy to enhance AAV-mediated gene therapy by enabling sustained transgene expression in degenerating retinas, improving treatment outcomes for patients with progressive vision loss.

Retinal Degeneration↗
PubMed2025

Biallelic loss-of-function variants in C19orf44 lead to retinal degeneration.

BACKGROUND: Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs. METHODS: All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to confirm identified variants. RESULTS: Three unrelated patients from Europe, Middle East and East Asia were identified with unique late-onset retinal degeneration (Stargardt-like phenotype) associated with biallelic loss-of-function (LoF) variants in C19orf44 (HGNC: 26141), a gene of unknown function. The homozygous variant NM_032207.2:c.549_550del;p.Ser185Profs*2 was identified in two unrelated patients (European and Middle Eastern). Moreover, an East Asian patient had likely compound heterozygous LoF variants (NM_032207.2:c.1168C>T;p.Gln390*/c.976_977del;p.Leu326Lysfs*15). CONCLUSIONS: Our findings establish C19orf44 as a novel disease-causing gene for IRD with Stargardt-like phenotype, expanding the genetic landscape of retinal degeneration.

Humans↗
PubMed1979

Permeability of retinal capillaries in rats with inherited retinal degeneration.

The permeability of retinal capillaries in RCS rats with inherited retinal degeneration was investigated with horseradish peroxidase used as a tracer. Five-week-old rats showed typical degeneration of photoreceptor cells and accumulation of outer segment debris, but retinal capillaries were not permeable to peroxidase. At 10 weeks of age, capillaries in the inner retina appeared normal, but many in the outer retina were leaky. Peroxidase activity in these latter vessels was demonstrable in the basal laminae of endothelial cells and pericytes and in vesicles on the luminal and abluminal sides of the endothelium. Tracer also permeated the intercellular spaces in the surrounding area. The number of leaky capillaries in the outer retina increased during the course of the dystrophy. The site of the leak in permeable capillaries has not yet been established; it may be due to an alteration of the endothelial cell junctions or of transcellular vesicular transport. In the choriocapillaris, peroxidase permeated Bruch's membrane and the basal infoldings between adjacent pigment epithelial cells; tracer progression along the intercellular spaces was blocked at the zonulae occludens at the apicolateral border. The RCS rat may be a useful model for studying the morphological basis of changes in capillary permeability associated with retinal degeneration.

Animals↗
PubMed1975

The role of retinol in, and the action of anti-inflammatory drugs on, hereditary retinal degeneration.

Light deprivation retarded retinal degeneration in albino dystrophic rats. In pigmented dystrophic rats the presence of pigment in the eye retarded the degenerative process. Retinol labilized rat retinal lysosomes in vitro. Acetylsalicylic acid stabilized retinal lysosomes even in the presence of the concentration of retinol which produced the maximum labilization. The effect of acetylsalicyclic acid was concentration dependent, maximum stabilization being produced by 0.25-0.50 mM. The results provide further evidence for the hypothesis that hereditary retinal degeneration in rats is mediated by an increased amount of retinol (produced by the action of light on an unusually labile type of visual pigment) causing a premature release of lysosomal enzymes.

Acid Phosphatase↗
PubMed1976

Primary retinal degeneration: evidence of normal phagocytosis in the retinal pigment epithelium.

In rats with primary retinal degeneration, lens extraction combined with total retinal detachment provided a model for injection of a tracer of colloidal carbon into the subretinal space. Electron microscopy and acid phosphatase cytochemistry were subsequently used to analyze the ingestion of tracer by the retinal pigment epithelium. It was found that the attachment, ingestion, and digestion phases of the phagocytic process were apparently preserved. From this evidence it is suggested that there is no lack of phagocytic power in the retinal pigment epithelium of affected rat strains.

Acid Phosphatase↗
PubMed1977

Complicated colobomatous microphthalmos in the BW rat: a new form of inherited retinal degeneration.

A new model of inherited retinal degeneration has been found in the rat. It is inherited in association with a number of other ocular defects, including microphthalmos, coloboma, retinal dysplasia, optic nerve hypoplasia and/or aplasia, as well as medullation of the nerve fiber layer of the retina. Together, these abnormalities constitute a condition referred to as complicated colobomatous microphthalmos. This condition was originally discovered in the Bmn strain of rats but subsequently transferred to a new genetic background in the Bmn-wys strain of rats (BW). This facilitated the histological evaluation of both the developmental and degenerative ocular defects in the adult animals. A well defined pattern emerged relating eye size, optic nerve size and retinal histology. Normal-sized eyes had normal-sized optic nerves and normal retinal histology while intermediate-sized eyes with no optic nerves had uniformly thin retinas. In contrast, intermediate-sized eyes with small optic nerves had areas of both normal thickness and thin retina. All of these eyes developed retinal degeneration characterized by a late onset and slow progression associated with normal phagocytic activity in the pigment epithelium and a tendency for the rod outer segments to fragment into very thin structures rather than accumulate as lamellar debris. This indicates that the retinal degeneration in the BW model differs in many respects from the well studied RCS model.

Animals↗
PubMed2024

Retinal Proteome Profiling of Inherited Retinal Degeneration Across Three Different Mouse Models Suggests Common Drug Targets in Retinitis Pigmentosa.

Inherited retinal degenerations (IRDs) are a leading cause of blindness among the population of young people in the developed world. Approximately half of IRDs initially manifest as gradual loss of night vision and visual fields, characteristic of retinitis pigmentosa (RP). Due to challenges in genetic testing, and the large heterogeneity of mutations underlying RP, targeted gene therapies are an impractical largescale solution in the foreseeable future. For this reason, identifying key pathophysiological pathways in IRDs that could be targets for mutation-agnostic and disease-modifying therapies (DMTs) is warranted. In this study, we investigated the retinal proteome of three distinct IRD mouse models, in comparison to sex- and age-matched wild-type mice. Specifically, we used the Pde6βRd10 (rd10) and RhoP23H/WT (P23H) mouse models of autosomal recessive and autosomal dominant RP, respectively, as well as the Rpe65-/- mouse model of Leber's congenital amaurosis type 2 (LCA2). The mice were housed at two distinct institutions and analyzed using LC-MS in three separate facilities/instruments following data-dependent and data-independent acquisition modes. This cross-institutional and multi-methodological approach signifies the reliability and reproducibility of the results. The large-scale profiling of the retinal proteome, coupled with in vivo electroretinography recordings, provided us with a reliable basis for comparing the disease phenotypes and severity. Despite evident inflammation, cellular stress, and downscaled phototransduction observed consistently across all three models, the underlying pathologies of RP and LCA2 displayed many differences, sharing only four general KEGG pathways. The opposite is true for the two RP models in which we identify remarkable convergence in proteomic phenotype even though the mechanism of primary rod death in rd10 and P23H mice is different. Our data highlights the cAMP and cGMP second-messenger signaling pathways as potential targets for therapeutic intervention. The proteomic data is curated and made publicly available, facilitating the discovery of universal therapeutic targets for RP.

Animals↗
PubMed1977

Clinical copper metabolism parameters in patients with retinitis pigmentosa and other tapeto-retinal degenerations.

Reports have appeared of abnormal copper metabolism in retinitis pigmentosa, and of a family with vitelliform retinal degeneration in which other members suffered from hepatolenticular degeneration. In the present study 15 patients with retinitis pigmentosa, 4 with various other retinal degenerations, and 1 with a family disposition to retinitis pigmentosa were examined. The copper concentration in serum and the coeruloplasmin concentration in plasma were found to be within normal limits. In 9 of the patients with retinitis pigmentosa the urinary excretion of copper per 24 hours was determined and was found to be normal. The results of the present study lend no support to the hypothesis of abnormal copper metabolism in retinitis pigmentosa.

Adolescent↗
PubMed1975

Continuous red light induces persistent estrus without retinal degeneration in the albino rat.

Female rats were exposed for 12 weeks to red (peak 660 nm) or Cool White continuous light (LL), or to 12 h per day (LD) of Cool White light, all at a flux density of 100 muw/cm2 (approximately 30 incident foot-candles). Either red or white LL produced significantly prolonged vaginal cornification and significantly reduced ovarian weight, as compared to LD exposure. White LL, but not red LL, produced degeneration of retinal photoreceptors.

Animals↗
PubMed1975

Total retinal degeneration in apparent anophthalmos of the Syrian hamster.

Anophthalmia in the Syrian hamster was found to result from an extensive degeneration of retinal tissue and tissues derived from the retina. Eyes of affected animals were normal at the twelfth day of gestation (the average gestation period in the Syrian hamster is 16 days). However, the retina of these eyes showed rapid and extensive degeneration during the first two weeks after birth. In adults, the sclera-choroid complex was the only prominent structure of the original eye, with an occasional remnant of deteriorated lens.

Animals↗
PubMed1975

A new form of hereditary retinal degeneration in Wag/Rij rats.

A spontaneous, hereditable, bilateral retinal degeneration affecting all adult animals in a closed, imbred colony of Wag/Rij rats has been discovered. The disorder is characterized by early onset and a slow progressive course. Early lesions are detected by one month in retinas which are otherwise fully developed. Destruction of the photoreceptor layer proceeds as more and more cells degenerate. Degeneration appears to begin in the photoreceptor cell body and only secondarily affects the outer segment. Futhermore, phagocytic activity of pigment epithelium remains intact until late in the disease. Endstage lesions include retinal disorganization, proliferation and vascularization of pigment epithelium, and migration of pigment epithilial cells into the retina. The temporal and structural characteristics of this retinopathy indicate it may serve as a useful model for study of retinitis pigmentosa in man.

Age Factors↗
PubMed1992

Drosophila retinal degeneration C (rdgC) encodes a novel serine/threonine protein phosphatase.

The Drosophila retinal degeneration C (rdgC) gene is required to prevent light-induced retinal degeneration. Molecular analysis shows that the rdgC transcription unit encodes a novel serine/threonine protein phosphatase. Amino acids 153-393 define a domain that has 30% identity with the catalytic domains of types 1, 2A, and 2B serine/threonine protein phosphatases. A putative regulatory domain is appended that contains multiple potential Ca(2+)-binding sites or "EF hand motifs." Thus, the analysis suggests that the rdgC protein is a novel type of serine/threonine protein phosphatase that is directly regulated by Ca2+. rdgC is expressed in the visual systems of the fly, as well as in the mushroom bodies of the central brain.

Amino Acid Sequence↗
PubMed1978

Electroretinography in pigmented rats with tapeto-retinal degeneration.

We studied tapeto-retinal degeneration in the offspring of Royal College of Surgeons (RCS) and Wistar albino rats. Normal ERG values vary according to skin pigmentation: thresholds and implicit times are different. We believe the best experimental material is to be found in the affected pigmented offspring. Evolution of the degeneration over more than 9 months has been observed before extinction and the expressivity of the disease varies from one individual to another. This animal model closely resembles the ERG findings observed clinically in certain pigmentary degenerations of the retina.

Albinism↗
PubMed1976

Senior-Loken syndrome (nephronophthisis and tapeto-retinal degeneration): a study of 8 cases from 5 families.

The association of nephronophthisis and tapeto-retional degeneration was described by both Senior and Loken in 1961, but prior to 1974 only 28 cases had been published. This report describes 8 new cases in 27 members of 5 families. The severe juvenile type produces blindness in infancy and death from renal failure before the age of ten. The adult type is characterized by later onset, slower progression of the renal disease and milder ocular manifestations. The eye disease may be congenital amaurosis of Leber type, pigmentary retinal degeneration or retinitis punctata albescens and the electroretinogram (ERG) is of value in the diagnosis of these varieties of hereditary tapeto-retinal degeneration. Renal involvement is often asymptomatic. Defective urinary concentration leading to polyuria and polydipsia is the earliest sign. Proteinuria is inconstant and urinary sediment is often normal. Two patients had aminoaciduria. The disease progresses inexorably to chronic renal failure. One patient has been successfully transplanted and two others are on chronic hemodialysis. Renal histological changes are those of nephronophthisis with tubulointerstitial lesions and multiple cysts. Senior-Loken syndrome appears to be transmitted by a single autosomal recessive pleotropic gene of variable expression. Degeneration of neuroepithelium and renal tubular epithelium, both tissues of ectodermal origin, may represent a genetically determined enzyme abnormality.

Adolescent↗
PubMed1978

Studies of visual function and its decay in mice with hereditary retinal degeneration.

Functional implications of mouse hereditary retinal degeneration have been studied at the level of the superior colliculus and visual cortex in the C57BL/6J-le rd strain. On autoradiography at a light-microscopic level, following eye injection with radioactive compounds, central visual structures appeared normal. A slight reduction in ipsilateral retinal projection was probably related to reduced retinal pigmentation associated with the light ear (le) mutation. In recordings from visual cortex and tectum in rd mice older than five months the cells discharged with highly rhythmic maintained activity. This ongoing activity depended on retinal input, since temporary asphyxia of the eye stopped it immediately. The frequency of the rhythm was influenced by the anesthesia. In these older mice no visual receptive fields could be mapped, but in a few tectal recordings it was possible to suppress the maintained activity by diffuse, very intense illumination. As in normal mice, no auditory or somatosensory responses were observed in the visual cortex or upper tectal layers. In recordings from tectum before the age of three weeks retinotopic topography and receptive fields were normal. By day 24 no receptive fields could be recorded from parts of the tectum representing the central 90--100 degrees of the visual field, whereas within a peripheral ring responses were still roughly normal under photopic conditions. Over the following four months these peripheral responses faded away slowly. Incremental thresholds, especially in the scotopic range, were elevated, rising slowly to unmeasurable values. Similarly during dark adaptation the thresholds fell to values several log units above those reached in normal mice; these values of dark adapted thresholds in rd mice rose with age. This is consistent with morphological changes known to occur in the retina as a consequence, of the rd mutation the rods degenerating before the cones.

Animals↗