Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.032
Filtrar
1.
Gene ; 851: 146956, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36341727

RESUMO

MOTIVATION: Next-generation sequencing (NGS) technologies are decisive for discovering disease-causing variants, although their cost limits their utility in a clinical setting. A cost-mitigating alternative is an extremely low coverage whole-genome sequencing (XLC-WGS). We investigated its use to identify causal variants within a multi-generational pedigree of individuals with retinitis pigmentosa (RP). Causing progressive vision loss, RP is a group of genetically heterogeneous eye disorders with approximately 60 known causal genes. RESULTS: We performed XLC-WGS in seventeen members of this pedigree, including three individuals with a confirmed diagnosis of RP. Sequencing data were processed using Illumina's DRAGEN pipeline and filtered using Illumina's genotype quality score metric (GQX). The resulting variants were analyzed using Expert Variant Interpreter (eVai) from enGenome as a prioritization tool. A nonsense known mutation (c.1625C > G; p.Ser542*) in exon 4 of the RP1 gene emerged as the most likely causal variant. We identified two homozygous carriers of this variant among the three sequenced RP cases and three heterozygous individuals with sufficient coverage of the RP1 locus. Our data show the utility of combining pedigree information with XLC-WGS as a cost-effective approach to identify disease-causing variants.


Assuntos
Proteínas do Olho , Retinite Pigmentosa , Humanos , Linhagem , Proteínas do Olho/genética , Análise Mutacional de DNA , Proteínas Associadas aos Microtúbulos/genética , Retinite Pigmentosa/genética , Retinite Pigmentosa/diagnóstico , Códon sem Sentido , Sequenciamento Completo do Genoma , Mutação
2.
Front Immunol ; 13: 1059947, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389729

RESUMO

Retinitis pigmentosa (RP) is an important cause of irreversible blindness worldwide and lacks effective treatment strategies. Although mutations are the primary cause of RP, research over the past decades has shown that neuroinflammation is an important cause of RP progression. Due to the abnormal activation of immunity, continuous sterile inflammation results in neuron loss and structural destruction. Therapies targeting inflammation have shown their potential to attenuate photoreceptor degeneration in preclinical models. Regardless of variations in genetic background, inflammatory modulation is emerging as an important role in the treatment of RP. We summarize the evidence for the role of inflammation in RP and mention therapeutic strategies where available, focusing on the modulation of innate immune signals, including TNFα signaling, TLR signaling, NLRP3 inflammasome activation, chemokine signaling and JAK/STAT signaling. In addition, we describe epigenetic regulation, the gut microbiome and herbal agents as prospective treatment strategies for RP in recent advances.


Assuntos
Degeneração Retiniana , Retinite Pigmentosa , Humanos , Doenças Neuroinflamatórias , Epigênese Genética , Retinite Pigmentosa/tratamento farmacológico , Retinite Pigmentosa/genética , Degeneração Retiniana/genética , Sistema Imunitário
3.
Genes (Basel) ; 13(11)2022 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-36360271

RESUMO

BACKGROUND: The presence of hyperreflective foci (HRF) in retinitis pigmentosa (RP) is a potentially new finding. We investigated the presence of HRF in SD-OCT images in eyes with RP and its relation to vascular, morphologic and metabolic findings in RP. METHODS: The study was performed on 42 RP patients and 24 controls. Using SD-OCT, we calculated the amount of HRF within the entire retina (HRF-ER) and the outer nuclear layer (HRF-ONL). Retinal vessel diameters (µm) and oxygen saturation (%) values were measured using Oxymap T1. We evaluated the mean diameter in retinal arterioles (D-A) and venules (D-V), the corresponding oxygen saturation values (A-SO2, V-SO2) and the oxygen saturation difference (A-V SO2). RESULTS: RP differed from controls by HRF-ER, HRF-ON and EZ-length (p < 0.001). D-A and D-V were narrower and A-SO2 and V-SO2 were higher in RP (p ≤ 0.001). Within RP, significant interactions were found between the HRF-ER* group and: BCVA, EZ length, D-A, A-SO2 and A-V SO2 (p ≤ 0.018). The HRF-ONL* group interactions were significant for: BCVA, EZ length, D-A, A-SO2 and A-V SO2 (p ≤ 0.014). CONCLUSION: The present study highlights the presence of HRF to reflect the vascular, morphologic and metabolic alterations in RP. These biomarkers seem to be associated with remodeling and apoptosis that occur with the progression of degeneration.


Assuntos
Oximetria , Retinite Pigmentosa , Humanos , Oximetria/métodos , Oxigênio/metabolismo , Retinite Pigmentosa/metabolismo , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/metabolismo , Retina/metabolismo
4.
Digit J Ophthalmol ; 28(3): 58-63, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405442

RESUMO

A 30-year-old woman with a phenotypic presentation of retinitis pigmentosa (RP) presented with a 5-day history of painless, acute vision loss in her right eye, with visual acuity dropping from 20/30 to hand motions. Optical coherence tomography of the right macula showed near-complete loss of the ellipsoid layer. Treatment with a prolonged course of oral prednisone resulted in a complete structural regeneration of the ellipsoid layer and improvement of visual acuity to 20/50, with eccentric fixation. Tests for infectious diseases, autoimmune disorders, and rare RP mimic syndromes (eg, Refsum disease) were negative. The patient has remained stable since. We favor a diagnosis of two separate pathologies and suggest a designation of acute zonal occult outer retinopathy (AZOOR) in RP for this previously unreported presentation.


Assuntos
Retinite Pigmentosa , Síndrome dos Pontos Brancos , Feminino , Humanos , Adulto , Síndrome dos Pontos Brancos/complicações , Síndrome dos Pontos Brancos/diagnóstico , Escotoma/diagnóstico , Escotoma/etiologia , Retinite Pigmentosa/complicações , Retinite Pigmentosa/diagnóstico , Tomografia de Coerência Óptica/métodos
5.
Mol Vis ; 28: 359-368, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36338669

RESUMO

Purpose: To identify the molecular mechanisms of the development of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance in an Israeli Muslim Arab family. Methods: Two patients with adRP underwent a detailed ophthalmic evaluation, including funduscopic examination, visual field testing, optical coherence tomography, and electroretinography. Genetic analysis was performed using a combination of whole exome sequencing (WES) and Sanger sequencing. The pathogenicity of the identified intronic variant was evaluated in silico using several web-based tools, in vitro using a minigene-based assay, and in vivo using reverse transcription PCR analysis of lymphocyte-derived RNA. The relative abundance of alternatively spliced transcripts was evaluated using amplicon-based next-generation sequencing. The relative expression levels of PRPF31 and CNOT3 were measured using quantitative PCR (qPCR) analysis. Results: The two patients recruited in this study had childhood-onset RP, with night blindness as the initial symptom, followed by concentric restriction of the visual field. The funduscopic findings included narrowed retinal blood vessels and peripheral bone spicule pigmentation. By the third decade of life, the full-field electroretinography findings had been remarkably attenuated. In these patients, we identified a novel heterozygous intronic variant at position +5 of PRPF31 intron 11 (c.1146+5G>T). The same variant was also detected in one asymptomatic family member. Through in silico analysis, the variant was predicted to alter the splicing of intron 11. An in vitro splicing assay and a reverse transcription PCR analysis of lymphocyte-derived RNA revealed that the mutant allele yielded mainly a shorter transcript in which exon 11 was skipped. The skipping of exon 11 was expected to cause a frameshift and an aberrant truncated protein (p.Tyr359Serfs*29). The qPCR analysis revealed reduced PRPF31 expression levels in the mutation carriers, without a significant difference between the affected patient and his asymptomatic brother. We evaluated several factors that have been suggested to correlate with non-penetrance of PRPF31 mutations, including the number of cis-acting MSR1 elements adjacent to the PRPF31 core promoter, CNOT3 expression level, and CNOT3 rs4806718 single-nucleotide polymorphism. None of these factors correlated with non-penetrance in the family in this study. Conclusions: We report a novel intronic mutation in PRPF31 underlying adRP. This report expands the spectrum of pathogenic mutations in PRPF31 and further demonstrates the importance of intronic mutations. Moreover, it demonstrates the phenomenon of incomplete penetrance previously associated with PRPF31 mutations. The fact that the non-penetrance in the family in this study could not be explained by any of the known mechanisms suggests the possible contribution of a novel modifier of PRPF31 penetrance.


Assuntos
Proteínas do Olho , Retinite Pigmentosa , Masculino , Humanos , Criança , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Linhagem , Retinite Pigmentosa/diagnóstico , Mutação/genética , RNA , Genes Dominantes , Fatores de Transcrição/genética
6.
BMC Ophthalmol ; 22(1): 441, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36384460

RESUMO

BACKGROUND: Usher syndrome (USH) is an autosomal recessive disorder primarily responsible for deaf-blindness. Patients with subtype Usher syndrome type 1 (USH1) typically experience congenital sensorineural hearing loss, abnormal vestibular function, and retinitis pigmentosa (RP). Here we present a case of Usher syndrome type 1F (USH1F) with a novel homozygous variant in the calcium-dependent cell-cell adhesion protocadherin-15 (PCDH15) gene. CASE PRESENTATION: Ophthalmic examinations were evaluated over a course of 10 years and the disease-causing variant was identified by whole exome sequencing (WES). Initial and follow-up examination of color fundus photos after 10 years revealed an increase in bone spicule pigment deposits in both eyes. A parafoveal hyper-AF ring in both eyes was shown in fundus autofluorescence (FAF) with a progressive diameter-wise constriction observed over 8 years. Outer nuclear layer (ONL) loss was observed in parafoveal and perifoveal regions of both eyes on spectral domain-optical coherence tomography (SD-OCT). Full-field electroretinography (ffERG) showed extinguished global retinal function. WES identified a novel two-base-pair deletion, c.60_61del (p.Phe21Ter), in the PCDH15 gene, confirming the diagnosis of USH1F. CONCLUSIONS: We report a novel homozygous PCDH15 pathogenic variant expected to lead to nonsense-mediated decay (NMD) of PCDH15 mRNA. The patient exhibits a loss of function with USH1F, experiencing congenital hearing loss and syndromic RP.


Assuntos
Retinite Pigmentosa , Síndromes de Usher , Humanos , Síndromes de Usher/diagnóstico , Síndromes de Usher/genética , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/genética , Retina , Caderinas/genética
7.
Int J Mol Sci ; 23(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36362148

RESUMO

Signal peptide (SP) mutations are an infrequent cause of inherited retinal diseases (IRDs). We report the genes currently associated with an IRD that possess an SP sequence and assess the prevalence of these variants in a multi-institutional retrospective review of clinical genetic testing records. The online databases, RetNet and UniProt, were used to determine which IRD genes possess a SP. A multicenter retrospective review was performed to retrieve cases of patients with a confirmed diagnosis of an IRD and a concurrent SP variant. In silico evaluations were performed with MutPred, MutationTaster, and the signal peptide prediction tool, SignalP 6.0. SignalP 6.0 was further used to determine the locations of the three SP regions in each gene: the N-terminal region, hydrophobic core, and C-terminal region. Fifty-six (56) genes currently associated with an IRD possess a SP sequence. Based on the records review, a total of 505 variants were present in the 56 SP-possessing genes. Six (1.18%) of these variants were within the SP sequence and likely associated with the patients' disease based on in silico predictions and clinical correlation. These six SP variants were in the CRB1 (early-onset retinal dystrophy), NDP (familial exudative vitreoretinopathy) (FEVR), FZD4 (FEVR), EYS (retinitis pigmentosa), and RS1 (X-linked juvenile retinoschisis) genes. It is important to be aware of SP mutations as an exceedingly rare cause of IRDs. Future studies will help refine our understanding of their role in each disease process and assess therapeutic approaches.


Assuntos
Doenças Retinianas , Distrofias Retinianas , Retinite Pigmentosa , Humanos , Sinais Direcionadores de Proteínas/genética , Doenças Retinianas/genética , Distrofias Retinianas/genética , Distrofias Retinianas/diagnóstico , Retina , Retinite Pigmentosa/genética , Testes Genéticos , Mutação , Linhagem , Análise Mutacional de DNA , Proteínas do Olho/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Receptores Frizzled/genética
8.
J Chem Inf Model ; 62(22): 5794-5805, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36367985

RESUMO

N-terminal P23H opsin mutation accounts for most of retinitis pigmentosa (RP) cases. P23H functions and folding can be rescued by small chaperone ligands, which contributes to validate mutant opsin as a suitable target for pharmacological treatment of RP. However, the lack of structural details on P23H mutant opsin strongly impairs drug design, and new chemotypes of effective chaperones of P23H opsin are in high demand. Here, a computational-boosted workflow combining homology modeling with molecular dynamics (MD) simulations and virtual screening was used to select putative P23H opsin chaperones among different libraries through a structure-based approach. In vitro studies corroborated the reliability of the structural model generated in this work and identified a number of novel chemotypes of safe and effective chaperones able to promote P23H opsin trafficking to the outer cell membrane.


Assuntos
Opsinas , Retinite Pigmentosa , Humanos , Opsinas/genética , Reprodutibilidade dos Testes , Opsinas de Bastonetes/química , Opsinas de Bastonetes/genética , Opsinas de Bastonetes/metabolismo , Retinite Pigmentosa/tratamento farmacológico , Retinite Pigmentosa/genética , Retinite Pigmentosa/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/uso terapêutico
9.
Turk J Med Sci ; 52(3): 741-746, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36326334

RESUMO

BACKGROUND: To investigate the effect of transcorneal electrical stimulation (TES) therapy in patients with retinitis pigmentosa (RP). METHODS: We performed TES therapy in 21 patients with RP in 12 sessions with 1-week intervals. The following parameters obtained before and after the TES therapy were compared statistically; the best corrected visual acuity (BCVA, logMAR), Ishihara color vision level, multifocal electroretinography (mf-ERG) response, automated visual field (VF) outcome, and the 25-item low vision quality-of-life (LVQOL) questionnaire points. RESULTS: The mean age of patients (6 females; 15 males) was 31.67 ± 9.80 years (20-50 years). While increases in BCVA level, color vision level, mf-ERG response in p1 amplitude of ring 1, and LVQOL questionnaire points were statistically significant, changes in VF test and other mf-ERG responses were not. Twenty of the patients (95.24%) stated that they were satisfied with the TES therapy. No considerable side effect was observed in any patient due to the therapy. DISCUSSION: The TES therapy may be an effective and safe treatment modality in slowing the RP progression, especially in the early stages of the disease. Longer-term follow-ups in larger patient populations are warranted.


Assuntos
Terapia por Estimulação Elétrica , Retinite Pigmentosa , Masculino , Feminino , Humanos , Acuidade Visual , Retinite Pigmentosa/terapia , Eletrorretinografia , Testes de Campo Visual , Retina
10.
Int J Mol Sci ; 23(19)2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-36233334

RESUMO

Mutations in C8orf37 cause Bardet-Biedl syndrome (BBS), retinitis pigmentosa (RP), and cone-rod dystrophy (CRD), all manifest in photoreceptor degeneration. Little is known about which proteins C8orf37 interacts with to contribute to photoreceptor survival. To determine the proteins that potentially interact with C8orf37, we carried out a yeast two-hybrid (Y2H) screen using C8orf37 as a bait. FAM161A, a microtubule-binding protein localized at the photoreceptor cilium required for photoreceptor survival, was identified as one of the preys. Double immunofluorescence staining and proximity ligation assay (PLA) of marmoset retinal sections showed that C8orf37 was enriched and was co-localized with FAM161A at the ciliary base of photoreceptors. Epitope-tagged C8orf37 and FAM161A, expressed in HEK293 cells, were also found to be co-localized by double immunofluorescence staining and PLA. Furthermore, interaction domain mapping assays identified that the N-terminal region of C8orf37 and amino acid residues 341-517 within the PFAM UPF0564 domain of FAM161A were critical for C8orf37-FAM161A interaction. These data suggest that the two photoreceptor survival proteins, C8orf37 and FAM161A, interact with each other which may contribute to photoreceptor health.


Assuntos
Proteínas do Olho , Proteínas , Retinite Pigmentosa , Aminoácidos/metabolismo , Epitopos/metabolismo , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Células HEK293 , Humanos , Células Fotorreceptoras/metabolismo , Proteínas/genética , Proteínas/metabolismo , Retinite Pigmentosa/genética , Retinite Pigmentosa/metabolismo
11.
EMBO Mol Med ; 14(11): e15941, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36194668

RESUMO

Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene-specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogenic events in IRDs; hence, approaches that enhance mitochondrial activities have a promising therapeutic potential for these conditions. We previously reported that miR-181a/b downregulation boosts mitochondrial turnover in models of primary retinal mitochondrial diseases. Here, we show that miR-181a/b silencing has a beneficial effect also in IRDs. In particular, the injection in the subretinal space of an adeno-associated viral vector (AAV) that harbors a miR-181a/b inhibitor (sponge) sequence (AAV2/8-GFP-Sponge-miR-181a/b) improves retinal morphology and visual function both in models of autosomal dominant (RHO-P347S) and of autosomal recessive (rd10) retinitis pigmentosa. Moreover, we demonstrate that miR-181a/b downregulation modulates the level of the mitochondrial fission-related protein Drp1 and rescues the mitochondrial fragmentation in RHO-P347S photoreceptors. Overall, these data support the potential use of miR-181a/b downregulation as an innovative mutation-independent therapeutic strategy for IRDs, which can be effective both to delay disease progression and to aid gene-specific therapeutic approaches.


Assuntos
MicroRNAs , Retinite Pigmentosa , Humanos , Regulação para Baixo , Retina/patologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/terapia , Retinite Pigmentosa/metabolismo , Mutação , MicroRNAs/genética , MicroRNAs/metabolismo
12.
Stem Cell Reports ; 17(11): 2409-2420, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36206764

RESUMO

Interphotoreceptor matrix proteoglycan 2 (IMPG2) mutations cause a severe form of early-onset retinitis pigmentosa (RP) with macular involvement. IMPG2 is expressed by photoreceptors and incorporated into the matrix that surrounds the inner and outer segments (OS) of rods and cones, but the mechanism of IMPG2-RP remains unclear. Loss of Impg2 function in mice produces a mild, late-onset photoreceptor phenotype without the characteristic OS loss that occurs in human patients. We generated retinal organoids (ROs) from patient-derived induced pluripotent stem (iPS) cells and gene-edited embryonic stem cells to model human IMPG2-RP in vitro. All ROs harboring IMPG2 mutations lacked an OS layer, in contrast to isogenic controls. Subsequent protein analyses revealed that this phenotype arises due to a loss of IMPG2 expression or its inability to undergo normal post-translational modifications. We hypothesized that loss of IMPG2 function destabilizes the interphotoreceptor matrix and renders the OS vulnerable to physical stressors, which is accentuated in the tissue culture environment. In support of this mechanism, transplantation of IMPG2 mutant ROs into the protected subretinal space of immunocompromised rodents restored OS production. Beyond providing a robust platform to study IMPG2-RP, this human RO model system may serve a broader role in honing strategies to treat advanced photoreceptor-based diseases.


Assuntos
Organoides , Retinite Pigmentosa , Humanos , Camundongos , Animais , Organoides/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas do Olho/genética , Proteoglicanas/genética , Retinite Pigmentosa/genética , Retina/metabolismo , Mutação , Células Fotorreceptoras Retinianas Cones/metabolismo , Fenótipo
13.
Stem Cell Reports ; 17(11): 2421-2437, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36240775

RESUMO

Usher syndrome-associated retinitis pigmentosa (RP) causes progressive retinal degeneration, which has no cure. The pathomechanism of Usher type 1B (USH1B)-RP caused by MYO7A mutation remains elusive because of the lack of faithful animal models and limited knowledge of MYO7A function. Here, we analyzed 3D retinal organoids generated from USH1B patient-derived induced pluripotent stem cells. Increased differential gene expression occurred over time without excessive photoreceptor cell death in USH1B organoids compared with controls. Dysregulated genes were enriched first for mitochondrial functions and then proteasomal ubiquitin-dependent protein catabolic processes and RNA splicing. Single-cell RNA sequencing revealed MYO7A expression in rod photoreceptor and Müller glial cells corresponding to upregulation of stress responses in NRL+ rods and apoptotic signaling pathways in VIM+ Müller cells, pointing to the defensive mechanisms that mitigate photoreceptor cell death. This first human model for USH1B-RP provides a representation of patient retina in vivo relevant for development of therapeutic strategies.


Assuntos
Organoides , Retinite Pigmentosa , Animais , Humanos , Miosina VIIa , Organoides/patologia , Patologia Molecular , Miosinas/genética , Miosinas/metabolismo , Retina/metabolismo , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Células Fotorreceptoras Retinianas Bastonetes/patologia
14.
PLoS One ; 17(10): e0276629, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36269735

RESUMO

Cystoid macular edema (CME) is a major cause of central visual deterioration in retinitis pigmentosa. The exact reason for CME and its prognostic significance in this patient population is unknown. We seek to find clues to answer these questions by examining the anatomical correlations between retinal cysts and retinal morphometric parameters in a cohort of patients with retinitis pigmentosa and CME. For this reason, 103 patients (196 eyes) with untreated cystoid macular edema (CME) were identified from a pool of 578 genotyped patients with retinitis pigmentosa. Image analyses were conducted using three central horizontal OCT scans of these patients to calculate cross-sectional areas of the retinal nerve fiber layer, outer retinal, inner retinal, cysts, and total retinal areas. Lengths of the ellipsoid zone and outer limiting membrane were also measured. Best-fit curves were derived for analyzing the factors playing a role in the size of the retinal cysts and the patients' visual acuity. Generalized Estimating Equation and multivariate linear regression analyses were conducted to determine the correlations between visual acuity, morphometric and clinical data, and the significant cyst size and visual acuity determinants. Twenty-five percent of the screened patients (103/578) had CME. Patients with autosomal dominant retinitis pigmentosa had the highest incidence of CME (43.6%, p<0.001) but also had the best visual acuity (20/34±20/30, p = 0.02). The total cyst area was 0.14±0.18 mm2. Outer retinal area (B = 0.214; p = 0.008), age (B = -0.003; p<0.001) and retinal nerve fiber area (B = 0.411; p = 0.005) were main determinants of the (r = 0.44; p<0.001) cyst size. Cysts resolved with progressing retinal degeneration. Length of the intact ellipsoid zone (B = -5.16E-5; p<0.001), the inheritance pattern (B = 0.04; p = 0.028) and retinal nerve fiber area (B = 0.751; p<0.001) were the main determinants of visual acuity. In patients with retinitis pigmentosa and cystoid macular edema, retinal nerve fiber layer thickness is associated with decreasing visual acuity and cyst size. This finding suggests that intraretinal cysts may compress retinal axons and cause subsequent visual loss in retinitis pigmentosa.


Assuntos
Cistos , Edema Macular , Doenças Retinianas , Retinite Pigmentosa , Humanos , Edema Macular/etiologia , Tomografia de Coerência Óptica/métodos , Retinite Pigmentosa/complicações , Retinite Pigmentosa/genética , Acuidade Visual , Doenças Retinianas/complicações , Cistos/complicações
15.
Invest Ophthalmol Vis Sci ; 63(11): 11, 2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36251317

RESUMO

Retinal degenerative diseases such as retinitis pigmentosa cause a progressive loss of photoreceptors that eventually prevents the affected person from perceiving visual sensations. The absence of a visual input produces a neural rewiring cascade that propagates along the visual system. This remodeling occurs first within the retina. Then, subsequent neuroplastic changes take place at higher visual centers in the brain, produced by either the abnormal neural encoding of the visual inputs delivered by the diseased retina or as the result of an adaptation to visual deprivation. While retinal implants can activate the surviving retinal neurons by delivering electric current, the unselective activation patterns of the different neural populations that exist in the retinal layers differ substantially from those in physiologic vision. Therefore, artificially induced neural patterns are being delivered to a brain that has already undergone important neural reconnections. Whether or not the modulation of this neural rewiring can improve the performance for retinal prostheses remains a critical question whose answer may be the enabler of improved functional artificial vision and more personalized neurorehabilitation strategies.


Assuntos
Plasticidade Neuronal , Degeneração Retiniana , Próteses Visuais , Humanos , Plasticidade Neuronal/fisiologia , Degeneração Retiniana/fisiopatologia , Degeneração Retiniana/reabilitação , Retinite Pigmentosa/fisiopatologia , Retinite Pigmentosa/reabilitação , Resultado do Tratamento
16.
Zhonghua Yan Ke Za Zhi ; 58(10): 788-792, 2022 Oct 11.
Artigo em Chinês | MEDLINE | ID: mdl-36220650

RESUMO

A 5-year-old female patient, presented with"night blindness and poor hearing for 1 year"whose first diagnosis was Usher syndrome due to retinitis pigmentosa accompanied by sensorineural deafness. Compound heterozygous variants (c.5G>A, p.W2*/c.3022C>T, p.P1008S) of PEX1, the causative gene for Zellweger spectrum disorder was confirmed by targeted exome sequencing analysis. Permanent tooth enamel dysplasia, nail leukoplakia, and biochemical abnormalities of peroxisome which is consistent with mild Zellweger spectrum disorder were found when she followed up.


Assuntos
Retinite Pigmentosa , Síndromes de Usher , Síndrome de Zellweger , ATPases Associadas a Diversas Atividades Celulares/genética , Pré-Escolar , Feminino , Testes Genéticos , Humanos , Proteínas de Membrana/genética , Mutação , Linhagem , Síndromes de Usher/genética , Síndrome de Zellweger/diagnóstico , Síndrome de Zellweger/genética
17.
Orphanet J Rare Dis ; 17(1): 378, 2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-36253797

RESUMO

BACKGROUND: Retinitis pigmentosa (RP) is a hereditary retinal disease which leads to visual impairment. The onset and progression of RP has physiological consequences that affects the ocular environment. Some of the key non-genetic factors which hasten the retinal degeneration in RP include oxidative stress, hypoxia and ocular inflammation. In this study, we investigated the status of the ocular immune privilege during retinal degeneration and the effect of ocular immune changes on the peripheral immune system in RP. We assessed the peripheral blood mononuclear cell stimulation by retinal antigens and their immune response status in RP patients. Subsequently, we examined alterations in ocular immune privilege machineries which may contribute to ocular inflammation and disease progression in rd1 mouse model. RESULTS: In RP patients, we observed a suppressed anti-inflammatory response to self-retinal antigens, thereby indicating a deviated response to self-antigens. The ocular milieu in rd1 mouse model indicated a significant decrease in immune suppressive ligands and cytokine TGF-B1, and higher pro-inflammatory ocular protein levels. Further, blood-retinal-barrier breakdown due to decrease in the expression of tight junction proteins was observed. The retinal breach potentiated pro-inflammatory peripheral immune activation against retinal antigens and caused infiltration of the peripheral immune cells into the ocular tissue. CONCLUSIONS: Our studies with RP patients and rd1 mouse model suggest that immunological consequences in RP is a contributing factor in the progression of retinal degeneration. The ocular inflammation in the RP alters the ocular immune privilege mechanisms and peripheral immune response. These aberrations in turn create an auto-reactive immune environment and accelerate retinal degeneration.


Assuntos
Degeneração Retiniana , Retinite Pigmentosa , Animais , Anti-Inflamatórios , Autoantígenos , Citocinas , Modelos Animais de Doenças , Privilégio Imunológico , Inflamação , Leucócitos Mononucleares/metabolismo , Camundongos , Proteínas de Junções Íntimas
18.
Technol Cancer Res Treat ; 21: 15330338221123109, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36254562

RESUMO

Objectives: The TNFAIP8 gene family and TNFAIP2 gene are inextricably linked to an elevated risk of cancer development. This systemic review and meta-analysis seeks to establish the relationship between TNFAIP8 (rs11064, rs1045241, rs1045242, and rs3813308), TNFAIP8L1 (rs1060555), and TNFAIP2 (rs710100 and rs8126) polymorphisms with the risk of cancer. Methods and Materials: A systematic search of multiple databases from January 2022 to April 2022 was used to identify relevant studies. Odds ratios (ORs) with corresponding 95% CI and p-value were calculated to assess the association. Bonferroni correction was performed to correct p-values. Trial sequential analysis (TSA) and in-silico messenger RNA expression were also performed. Review Manager 5.4 software was used for performing this meta-analysis. Results: This study comprised 6909 cancer patients and 7087 healthy participants from 14 studies. Four genetic models of rs11064 (codominant 2 [COD2]: OR = 2.30, p = 7.83 × 10-5; codominant 3 [COD3]: OR = 2.10, p = .0006; recessive model [RM]: OR = 2.24, p = .0001; AC: OR = 1.47, p = .037), two genetic models of rs1045241 (codominant 1 [COD1]: OR = 1.27, p = .009; overdominant model [ODM]: OR = 1.24, p = .018), four genetic models of rs1045242 (COD1: OR = 1.52, p = .005; dominant model (DM): OR = 1.56, p = .002; OD: OR = 1.48, p = .008; AC: OR = 1.48, p = .002), and three genetic models of rs8126 (COD2: OR = 1.41, p = .0005; COD3: OR = 1.44, p = .0002; RM: OR = 1.43, p = .0001) were statistically linked to cancer risk. Only one genetic model of rs1060555 polymorphism showed a significant protective association with cancer (COD2: OR = 0.80, p = .048). The outcomes of TSA also validated the findings of the meta-analysis. Conclusion: This study summarizes that rs11064, rs1045241, and rs1045242 polymorphisms of TNFAIP8 gene and rs8126 polymorphism of TNFAIP2 gene are significantly linked with the risk of cancer development. This meta-analysis was registered at INPLASY (registration number: INPLASY202270073).


Assuntos
Predisposição Genética para Doença , Neoplasias , Benzopiranos , Estudos de Casos e Controles , Citocinas/genética , Humanos , Neoplasias/genética , Fenóis , Polimorfismo de Nucleotídeo Único , RNA Mensageiro , Retinite Pigmentosa
19.
Int J Mol Sci ; 23(18)2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36142423

RESUMO

Precise genetic diagnosis in RPE65-mediated retinitis pigmentosa (RP) is necessary to establish eligibility for genetic treatment with voretigene neparvovec: a recombinant adeno-associated viral vector providing a functional RPE65 gene. This case report aims to report a novel RP-related point mutation RPE65 c.353G>A, p.(Arg118Lys), a variant of uncertain significance associated with a severe clinical presentation and the striking phenotypic feature of complete macular atrophy. We report the case of a 40-year-old male with inherited retinal dystrophy, all features typical for the RPE65-associated RP, and marked macular atrophy. Genetic testing identified that the patient was a compound heterozygote in trans form with two heterozygous variants: RPE65 c.499G>T, p.(Asp167Tyr) and RPE65 c.353G>A, p.(Arg118Lys). Furthermore, short-wavelength and near-infrared autofluorescence patterns exhibited deficiencies specific to mutations in the visual cycle genes. To the best of our knowledge, RPE65 c.353G>A, p.(Arg118Lys) is the first described point mutation on this locus, among all other reported insertional mutations, currently classified as likely benign and of uncertain significance. We concluded that this variant contributed to the pathological phenotype, demonstrating its significance clearly to be reclassified as likely pathogenic. This being the case, patients with this specific variant in homozygous or compound heterozygous form would be likely candidates for genetic treatment with voretigene neparvovec.


Assuntos
Distrofias Retinianas , Retinite Pigmentosa , Atrofia , Humanos , Masculino , Mutação , Mutação Puntual , Distrofias Retinianas/genética , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , cis-trans-Isomerases/genética
20.
PLoS One ; 17(9): e0274066, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36083972

RESUMO

BACKGROUND: Retinitis pigmentosa (RP) is the most frequent retinal hereditary dystrophy and result in blindness if progresses. Several case reports have revealed the possible association between RP and primary angle-closure glaucoma (PACG). We conducted a population-based study to explore whether RP significantly increased the risk of PACG development. METHODS: Using the Taiwan National Health Insurance Research Database, we enrolled patients with RP into the RP group from 2001 to 2013 and included a comparison group of 1:4 age- and sex-matched individuals without RP. We performed a Cox regression analysis to estimate the crude and adjusted hazard ratios (HRs) of RP for PACG after adjustment for hypertension, diabetes, hyperlipidaemia, chronic kidney disease, and lens subluxation. RESULTS: We enrolled 6223 subjects with RP and 24892 subjects for comparison. The mean age of the cohort was 49.0 ± 18.1 years. The RP group had significantly higher percentages of diabetes mellitus, hypertension, and hyperlipidaemia. The cumulative incidence of PACG in patients with RP was 1.61%, which was significantly higher than that in the comparison group (0.81%, p < 0.0001). According to the univariate Cox regression analysis, the hazard of PACG development was significantly greater in the RP group, with an unadjusted HR of 2.09 (95% confidence interval [CI], 1.64-2.65). The increased risk persisted after adjusting for confounders (adjusted HR = 2.18; 95% CI, 1.76-2.72). CONCLUSION: This nationwide population-based cohort study showed that people with RP are at a significantly greater risk of developing PACG than individuals without RP.


Assuntos
Diabetes Mellitus , Glaucoma de Ângulo Fechado , Hiperlipidemias , Hipertensão , Retinite Pigmentosa , Adulto , Idoso , Estudos de Coortes , Glaucoma de Ângulo Fechado/complicações , Glaucoma de Ângulo Fechado/epidemiologia , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/epidemiologia , Hipertensão/complicações , Hipertensão/epidemiologia , Pessoa de Meia-Idade , Retinite Pigmentosa/complicações , Retinite Pigmentosa/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...