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Ophthalmic Genetics Apr 2024ATF6-associated Achromatopsia (ACHM) is a rare autosomal recessive disorder characterized by reduction of visual acuity, photophobia, nystagmus, and poor color vision.
BACKGROUND
ATF6-associated Achromatopsia (ACHM) is a rare autosomal recessive disorder characterized by reduction of visual acuity, photophobia, nystagmus, and poor color vision.
METHODS
Detailed ophthalmological examinations were performed in a Chinese patient with ACHM. Whole exome sequencing and Sanger sequencing were performed to detect the disease-causing gene in the patient.
RESULTS
A 6-year-old girl presented photophobia, low vision and reduced color discrimination. Small yellow lesion in the macula of both eyes was observed. FAF demonstrated hypofluorescence in the macular fovea. OCT images revealed interruption of ellipsoid and interdigitation zone in the foveal area and a loss of the foveal pit. ERG showed relatively normal rod responses and unrecordable cone responses. Sequencing result identified a novel splicing variant c.354 + 6T>C in the ATF6 gene (NM_007348.4).
CONCLUSIONS
We reported detailed clinical features and genetic analysis of a new Chinese ATF6-associated patient with ACHM.
Topics: Child; Female; Humans; Activating Transcription Factor 6; China; Color Vision Defects; Photophobia; Retinal Cone Photoreceptor Cells; Tomography, Optical Coherence
PubMed: 38419580
DOI: 10.1080/13816810.2024.2322643 -
Frontiers in Cellular Neuroscience 2024The vertebrate retina is made up of six specialized neuronal cell types and one glia that are generated from a common retinal progenitor. The development of these... (Review)
Review
The vertebrate retina is made up of six specialized neuronal cell types and one glia that are generated from a common retinal progenitor. The development of these distinct cell types is programmed by transcription factors that regulate the expression of specific genes essential for cell fate specification and differentiation. Because of the complex nature of transcriptional regulation, understanding transcription factor functions in development and disease is challenging. Research on the transcription factor CRX provides an excellent model to address these challenges. In this review, we reflect on 25 years of mammalian CRX research and discuss recent progress in elucidating the distinct pathogenic mechanisms of four coding variant classes. We highlight how biochemical studies of CRX protein functions facilitate understanding CRX regulatory principles in animal models. We conclude with a brief discussion of the emerging systems biology approaches that could accelerate precision medicine for -linked diseases and beyond.
PubMed: 38414750
DOI: 10.3389/fncel.2024.1347436 -
International Journal of Molecular... Feb 2024It is unclear whether normal human skin tissue or abnormal scarring are photoreceptive. Therefore, this study investigated photosensitivity in normal skin tissue and...
It is unclear whether normal human skin tissue or abnormal scarring are photoreceptive. Therefore, this study investigated photosensitivity in normal skin tissue and hypertrophic scars. The expression of opsins, which are photoreceptor proteins, in normal dermal fibroblasts (NDFs) and hypertrophic scar fibroblasts (HSFs) was examined. After exposure to blue light (BL), changes in the expression levels of and clock-related genes, specifically and , were examined in both fibroblast types. Opsins were expressed in both fibroblast types, with OPN3 exhibiting the highest expression levels. After peripheral circadian rhythm disruption, BL induced rhythm formation in NDFs. In contrast, although HSFs showed changes in clock-related gene expression levels, no distinct rhythm formation was observed. The expression level of was significantly higher in HSFs and decreased to the same level as that in NDFs upon BL exposure. When OPN3 knocked-down HSFs were exposed to BL, the reduction in expression was inhibited. This study showed that BL exposure directly triggers peripheral circadian synchronization in NDFs but not in HSFs. OPN3-mediated BL exposure inhibited HSFs. Although the current results did not elucidate the relationship between peripheral circadian rhythms and hypertrophic scars, they show that BL can be applied for the prevention and treatment of hypertrophic scars and keloids.
Topics: Humans; Cicatrix, Hypertrophic; Skin; Keloid; Fibroblasts; Opsins; Rod Opsins
PubMed: 38396801
DOI: 10.3390/ijms25042126 -
The American Journal of Pathology May 2024α-Synuclein (α-Syn) is a key determinator of Parkinson disease (PD) pathology, but synapse and microcircuit pathologies in the retina underlying visual dysfunction are...
α-Synuclein (α-Syn) is a key determinator of Parkinson disease (PD) pathology, but synapse and microcircuit pathologies in the retina underlying visual dysfunction are poorly understood. Herein, histochemical and ultrastructural analyses and ophthalmologic measurements in old transgenic M83 PD model (mice aged 16 to 18 months) indicated that abnormal α-Syn aggregation in the outer plexiform layer (OPL) was associated with degeneration in the C-terminal binding protein 2 (CtBP2) ribbon synapses of photoreceptor terminals and protein kinase C alpha (PKCα) rod bipolar cell terminals, whereas α-Syn aggregates in the inner retina correlated with the reduction and degeneration of tyrosine hydroxylase- and parvalbumin-positive amacrine cells. Phosphorylated Ser129 α-synuclein expression was strikingly restricted in the OPL, with the most severe degenerations in the entire retina, including mitochondrial degeneration and loss of ribbon synapses in 16- to 18-month-old mice. These synapse- and microcircuit-specific deficits of the rod pathway at the CtBP2 rod terminals and PKCα rod bipolar and amacrine cells were associated with attenuated a- and b-wave amplitudes and oscillatory potentials on the electroretinogram. They were also associated with the impairment of visual functions, including reduced contrast sensitivity and impairment of the middle range of spatial frequencies. Collectively, these findings demonstrate that α-Syn aggregates cause the synapse- and microcircuit-specific deficits of the rod pathway and the most severe damage to the OPL, providing the retinal synaptic and microcircuit basis for visual dysfunctions in PD.
Topics: Animals; Mice; alpha-Synuclein; Amacrine Cells; Protein Kinase C-alpha; Retina; Retinal Rod Photoreceptor Cells; Synapses; Transcription Factors
PubMed: 38395146
DOI: 10.1016/j.ajpath.2024.01.017 -
Retinal Cases & Brief Reports Feb 2024To report a case of clinically diagnosed cancer-associated retinopathy (CAR) successfully treated with intravitreal corticosteroid implants without systemic...
Successful Treatment of Clinically Diagnosed Cancer-Associated Retinopathy with Intravitreal Dexamethasone Implant Followed by 0.18 mg Fluocinolone Implant without Systemic Immunosuppression.
PURPOSE
To report a case of clinically diagnosed cancer-associated retinopathy (CAR) successfully treated with intravitreal corticosteroid implants without systemic immunosuppression.
METHODS
Case report with multimodal imaging.
RESULTS
An 80-year-old man without known systemic malignancy presented with debilitating shimmering, hemeralopia and rapidly progressive bilateral vision loss following uncomplicated cataract surgery. Mild vitritis, extensive photoreceptor loss, mottling of retinal pigmentary epithelium (RPE), and mild vascular attenuation were found in both eyes. Full field electroretinogram (ffERG) showed severe bilateral rod-cone dysfunction. Infectious etiologies and vitreoretinal lymphoma were ruled out. During cancer workup, intravitreal corticosteroid treatment was offered. Significant anatomical improvement with reconstitution of ellipsoid zone, improved RPE irregularities and functional improvement, were observed 3 weeks after bilateral intravitreal dexamethasone implants (Ozurdex). 2 months later, patient received bilateral intravitreal 0.18mg fluocinolone acetonide implants (YUTIQ). Later, a colonic adenocarcinoma was found (pathologic stage pT3 pN0). Patient recovered well from surgery and no chemotherapy was needed. 9 months since bilateral intravitreal fluocinolone acetonide implants (11 months since bilateral intravitreal dexamethasone implants), best corrected vision maintained at 20/25-2 OD, 20/20 OS without ongoing treatments. Bilateral reconstitution of ellipsoid zones and nearly resolution of RPE irregularities remained stable. Repeat ffERG demonstrated improved cone response OS and stable diminished rod response OU. Patient reports resolution of ocular symptoms.
CONCLUSION
The sustained improvements with intravitreal corticosteroid monotherapy suggest potential advantages using local therapy over systemic treatment. Long term follow-up is warranted. Further research is needed to evaluate the efficacy of using 0.18mg fluocinolone implant (YUTIQ) to treat CAR.
PubMed: 38386915
DOI: 10.1097/ICB.0000000000001552 -
Frontiers in Cellular Neuroscience 2024Retinitis pigmentosa (RP) is a form of retinal degeneration characterized by primary degeneration of rod photoreceptors followed by a secondary cone loss that leads to... (Review)
Review
Retinitis pigmentosa (RP) is a form of retinal degeneration characterized by primary degeneration of rod photoreceptors followed by a secondary cone loss that leads to vision impairment and finally blindness. This is a rare disease with mutations in several genes and high genetic heterogeneity. A challenging effort has been the characterization of the molecular mechanisms underlying photoreceptor cell death during the progression of the disease. Some of the cell death pathways have been identified and comprise stress events found in several neurodegenerative diseases such as oxidative stress, inflammation, calcium imbalance and endoplasmic reticulum stress. Other cell death mechanisms appear more relevant to photoreceptor cells, such as high levels of cGMP and metabolic changes. Here we review some of the cell death pathways characterized in the RP mutant retina and discuss preclinical studies of therapeutic approaches targeting the molecular outcomes that lead to photoreceptor cell demise.
PubMed: 38370034
DOI: 10.3389/fncel.2024.1343544 -
Genome Research Mar 2024Dozens of variants in the gene for the homeodomain transcription factor (TF) cone-rod homeobox () are linked with human blinding diseases that vary in their severity and...
Dozens of variants in the gene for the homeodomain transcription factor (TF) cone-rod homeobox () are linked with human blinding diseases that vary in their severity and age of onset. How different variants in this single TF alter its function in ways that lead to a range of phenotypes is unclear. We characterized the effects of human disease-causing variants on CRX -regulatory function by deploying massively parallel reporter assays (MPRAs) in mouse retina explants carrying knock-ins of two variants, one in the DNA-binding domain (p.R90W) and the other in the transcriptional effector domain (p.E168d2). The degree of reporter gene dysregulation in these mutant retinas corresponds with their phenotypic severity. The two variants affect similar sets of enhancers, and p.E168d2 has distinct effects on silencers. -regulatory elements (CREs) near cone photoreceptor genes are enriched for silencers that are derepressed in the presence of p.E168d2. Chromatin environments of CRX-bound loci are partially predictive of episomal MPRA activity, and distal elements whose accessibility increases later in retinal development are enriched for CREs with silencer activity. We identified a set of potentially pleiotropic regulatory elements that convert from silencers to enhancers in retinas that lack a functional CRX effector domain. Our findings show that phenotypically distinct variants in different domains of CRX have partially overlapping effects on its -regulatory function, leading to misregulation of similar sets of enhancers while having a qualitatively different impact on silencers.
Topics: Animals; Humans; Mice; Homeodomain Proteins; Regulatory Sequences, Nucleic Acid; Retina; Retinal Cone Photoreceptor Cells; Trans-Activators; Transcription Factors
PubMed: 38355306
DOI: 10.1101/gr.278133.123 -
Ophthalmic & Physiological Optics : the... May 2024To explore the mechanisms of cone sensitivity loss in retinitis pigmentosa by combining two-colour perimetry with threshold versus intensity (tvi) testing.
PURPOSE
To explore the mechanisms of cone sensitivity loss in retinitis pigmentosa by combining two-colour perimetry with threshold versus intensity (tvi) testing.
METHODS
Seven subjects with autosomal recessive retinitis pigmentosa and 10 normal subjects were recruited and underwent perimetric testing of one eye using 480- and 640-nm Goldman size V targets presented under scotopic conditions (no background illumination) and against a white background ranging in luminance from -1.5 to 2 log cd m in 0.5 log cd m steps. Data were fitted with tvi functions of the form logT = logT + log ((A + A)/A), where T is the threshold, T is the absolute threshold, A is the background intensity, A is the 'dark-light' constant and n is a gain constant.
RESULTS
Reliable tvi functions could not be obtained within the region of the visual field corresponding to loss of the ellipsoid zone on optical coherence tomography. At fixation, changes in both T and A were observed, consistent with a d mechanism loss, which resulted in an upwards and rightwards shift of the tvi function. Losses at [±3°, ±3°] demonstrated changes in T, consistent with a d mechanism loss, resulting in an upwards translation of the tvi curve.
CONCLUSIONS
Although the absolute cone threshold was elevated at each location, shifts in the tvi function (so-called d mechanism loss) at fixation minimise threshold elevation in the presence of white adapting backgrounds, such as those typically employed in standard two-colour perimetry. At more peripheral testing locations, changes in threshold occurred independent of background luminance (so-called d mechanism loss). These findings suggest that backgrounds which selectively adapt rods while maintaining cones at, or near, absolute threshold may be preferable to conventional two-colour perimetry for assessing loss of cone sensitivity, especially at the point of fixation.
Topics: Humans; Dark Adaptation; Retinal Cone Photoreceptor Cells; Retinitis Pigmentosa; Visual Fields; Vision, Ocular; Visual Field Tests; Electroretinography
PubMed: 38351866
DOI: 10.1111/opo.13280 -
Bulletin of Mathematical Biology Feb 2024Both the rod and cone photoreceptors, along with the retinal pigment epithelium have been experimentally and mathematically shown to work interdependently to maintain...
Both the rod and cone photoreceptors, along with the retinal pigment epithelium have been experimentally and mathematically shown to work interdependently to maintain vision. Further, the theoredoxin-like rod-derived cone viability factor (RdCVF) and its long form (RdCVFL) have proven to increase photoreceptor survival in experimental results. Aerobic glycolysis is the primary source of energy production for photoreceptors and RdCVF accelerates the intake of glucose into the cones. RdCVFL helps mitigate the negative effects of reactive oxidative species and has shown promise in slowing the death of cones in mouse studies. However, this potential treatment and its effects have never been studied in mathematical models. In this work, we examine an optimal control with the treatment of RdCVFL. We mathematically illustrate the potential this treatment might have for treating degenerative retinal diseases such as retinitis pigmentosa, as well as compare this to the results of an updated control model with RdCVF.
Topics: Animals; Mice; Models, Biological; Mathematical Concepts; Retina; Retinal Cone Photoreceptor Cells; Retinitis Pigmentosa
PubMed: 38345678
DOI: 10.1007/s11538-024-01256-6 -
Journal of Visualized Experiments : JoVE Jan 2024Transplantation of photoreceptor cells and retinal pigment epithelial (RPE) cells provide a potential therapy for retinal degeneration diseases. Subretinal...
Transplantation of photoreceptor cells and retinal pigment epithelial (RPE) cells provide a potential therapy for retinal degeneration diseases. Subretinal transplantation of therapeutic donor cells into mouse recipients is challenging due to the limited surgical space allowed by the small volume of the mouse eye. We developed a trans-scleral surgical transplantation platform with direct transpupillary vision guidance to facilitate the subretinal delivery of exogenous cells in mouse recipients. The platform was tested using retinal cell suspensions and three-dimensional retinal sheets collected from rod-rich Rho::EGFP mice and cone-rich OPN1LW-EGFP;NRL mice, respectively. Live/dead assay showed low cell mortality for both forms of donor cells. Retinal grafts were successfully delivered into the subretinal space of a mouse model of retinal degeneration, Rd1/NS, with minimum surgical complications as detected by multimodal confocal scanning laser ophthalmoscope (cSLO) imaging. Two months post-transplantation, histological staining demonstrated evidence of advanced maturation of the retinal grafts into 'adult' rods and cones (by robust Rho::EGFP, S-opsin, and OPN1LW:EGFP expression, respectively) in the subretinal space. Here, we provide a surgical platform that can enable highly accurate subretinal delivery with a low rate of complications in mouse recipients. This technique offers precision and relative ease of skill acquisition. Furthermore, the technique could be used not only for studies of subretinal cell transplantation but also for other intraocular therapeutic studies including gene therapies.
Topics: Mice; Animals; Retinal Degeneration; Retina; Retinal Cone Photoreceptor Cells; Cell Transplantation; Vision, Ocular
PubMed: 38345250
DOI: 10.3791/65448