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Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third (n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families-all from the United States-showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no "region of overlap" among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.
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Defeitos da Visão Cromática , Opsinas de Bastonetes , Defeitos da Visão Cromática/genética , Deleção de Genes , Humanos , Família Multigênica/genética , Células Fotorreceptoras Retinianas Cones , Opsinas de Bastonetes/genéticaRESUMO
PURPOSE: Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian descent with only few reports of North African descent. METHODS: Genome, targeted next-generation, and Sanger sequencing was applied to cohort of â¼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium cells, and zebrafish. Variants' pathogenicity was accessed using 3D-modeling and/or ROs. RESULTS: Here, we identified a novel gene defect with three distinct pathogenic variants in UBAP1L in 4 independent autosomal recessive IRD cases from Tunisia. UBAP1L is expressed in the retinal pigment epithelium and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin-associated domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the solenoid of overlapping ubiquitin-associated domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein. CONCLUSION: Biallelic UBAP1L variants are a novel cause of IRDs, most likely enriched in the North African population.
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Distrofias de Cones e Bastonetes , Linhagem , Peixe-Zebra , Humanos , Distrofias de Cones e Bastonetes/genética , Distrofias de Cones e Bastonetes/patologia , Masculino , Feminino , Peixe-Zebra/genética , Animais , Genes Recessivos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Mutação/genética , Células Fotorreceptoras Retinianas Cones/patologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Retina/patologia , Retina/metabolismo , Adulto , Tunísia , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Fenótipo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologiaRESUMO
PURPOSE: To describe the clinical outcome and late-stage findings of extensive macular atrophy with pseudodrusen-like appearance (EMAP). DESIGN: Retrospective cohort study. PARTICIPANTS: Seventy-eight patients (156 eyes) affected by EMAP. METHODS: We collected data on best-corrected visual acuity, kinetic perimetry, OCT, short-wavelength autofluorescence, and near-infrared autofluorescence findings. Genetic testing for the TIMP3 and C1QTNF5 genes was performed via Sanger sequencing for 58 patients, with no pathogenic variants identified. MAIN OUTCOME MEASURES: The primary outcomes were best-corrected visual acuity at the last examination, visual field at the last examination, and incidence rates and time-to-event curves for blindness with the United States Social Security Administration and World Health Organization (WHO) criteria, foveal involvement, and atrophy enlargement beyond the 30° and 55° field of view. Imaging findings at the last examination were secondary outcomes. RESULTS: At the most recent visit, mean age was 70.9 ± 5.2 years. Using United States criteria, 58.1% of the patients were blind, and 25.8% were blind according to WHO criteria. All eyes showed large central scotomas, which were associated with visual field constriction in 22.2% of eyes. We detected focal openings or large dehiscences of Bruch's membrane (BM) in 25.4% of eyes. Near-infrared autofluorescence showed increased visibility of the choroidal vessels beyond the atrophy in 87.2% of eyes. The incidence rates for blindness were 3.95 per 100 patient-years with United States criteria and 1.54 per 100 patient-years according to WHO criteria. The incidence rates were 22.8 per 100 eye-years for foveal involvement, 12.0 per 100 eye-years for atrophy enlargement beyond 30°, and 6.6 per 100 eye-years for atrophy enlargement beyond 55°. The estimates were not influenced by the age at onset. CONCLUSIONS: We identified characteristic imaging findings, including BM ruptures, in elder patients with EMAP and calculated incidence rates for different functional and anatomic outcomes. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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INTRODUCTION: The aim of this study was to evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed ABCA4-associated Stargardt disease type 1 (STGD1) over a 24-month period in a multicenter prospective cohort study. METHODS: SD-OCT images from 428 eyes of 236 patients were analyzed. Change of mean thickness (MT) and intact area were estimated after semiautomated segmentation for the following individual layers in the central subfield (CS), inner ring (IR), and outer ring (OR) of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OSs), inner segments (IS), outer nuclear layer (ONL) inner retina (IR), and total retina. RESULTS: Statistically significant decreases of all outer retinal layers (RPE, OS, IS, and ONL) could be observed over a 24-month period both in decline of mean retinal thickness and intact area (p < 0.0001, respectively), whereas the IR showed an increase of retinal thickness in the CS and IR and remained unchanged in the OR. CONCLUSIONS: Significant loss could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with STGD1. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of STGD1.
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Progressão da Doença , Degeneração Macular , Epitélio Pigmentado da Retina , Doença de Stargardt , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Tomografia de Coerência Óptica/métodos , Doença de Stargardt/diagnóstico , Masculino , Estudos Prospectivos , Feminino , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Degeneração Macular/diagnóstico , Degeneração Macular/congênito , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/diagnóstico por imagem , Adolescente , Seguimentos , Retina/diagnóstico por imagem , Retina/patologia , CriançaRESUMO
INTRODUCTION: The purpose of this project was to explore the current standards of clinical care genetic testing and counseling for patients with inherited retinal diseases (IRDs) from the perspective of leading experts in selected European countries. Also, to gather opinions on current bottlenecks and future solutions to improve patient care. METHODS: On the initiative of the European Vision Institute, a survey questionnaire with 41 questions was designed and sent to experts in the field from ten European countries. Each participant was asked to answer with reference to the situation in their own country. RESULTS: Sixteen questionnaires were collected by November 2023. IRD genetic tests are performed in clinical care settings for 80% or more of tested patients in 9 countries, and the costs of genetic tests in clinical care are covered by the public health service to the extent of 90% or more in 8 countries. The median proportion of patients who are genetically tested, the median rate of genetically solved patients among those who are tested, and the median proportion of patients receiving counseling are 51-70%, 61-80%, and 61-80%, respectively. Improving the education of healthcare professionals who facilitate patient referrals to specialized centers, improving access of patients to more thorough genotyping, and increasing the number of available counselors were the most advocated solutions. CONCLUSION: There is a significant proportion of IRD patients who are not genetically tested, whose genetic testing is inconclusive, or who do not receive counseling. Educational programs, greater availability of state-of-the-art genotyping and genetic counselors could improve healthcare for IRD patients.
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Testes Genéticos , Doenças Retinianas , Humanos , Testes Genéticos/métodos , Europa (Continente) , Doenças Retinianas/genética , Doenças Retinianas/diagnóstico , Inquéritos e Questionários , Aconselhamento GenéticoRESUMO
Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.
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Oftalmopatias Hereditárias/genética , Proteínas de Ligação ao GTP/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação com Perda de Função , Miopia/genética , Proteínas do Tecido Nervoso/genética , Cegueira Noturna/genética , Adulto , Alelos , Processamento Alternativo , Encéfalo/metabolismo , Linhagem Celular , Criança , Pré-Escolar , Diagnóstico Diferencial , Saúde da Família , Feminino , França , Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/metabolismo , Glucose/metabolismo , Humanos , Secreção de Insulina , Masculino , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Pâncreas/metabolismo , Linhagem , Retina/metabolismo , Arábia Saudita , SenegalRESUMO
We assessed genotype-phenotype correlations among the visual, auditory, and olfactory phenotypes of 127 participants with Usher syndrome (USH2) (n =80) or nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) (n = 47) due to USH2A variants, using clinical data and molecular diagnostics from the Rate of Progression in USH2A Related Retinal Degeneration (RUSH2A) study. USH2A truncating alleles were associated with USH2 and had a dose-dependent effect on hearing loss severity with no effect on visual loss severity within the USH2 subgroup. A group of missense alleles in an interfibronectin domain appeared to be hypomorphic in ARRP. These alleles were associated with later age of onset, larger visual field area, better sensitivity thresholds, and better electroretinographic responses. No effect of genotype on the severity of olfactory deficits was observed. This study unveils a unique, tissue-specific USH2A allelic hierarchy with important prognostic implications for patient counseling and treatment trial endpoints. These findings may inform clinical care or research approaches in others with allelic disorders or pleiotropic phenotypes.
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Retinose Pigmentar , Síndromes de Usher , Proteínas da Matriz Extracelular/genética , Estudos de Associação Genética , Humanos , Mutação , Retinose Pigmentar/genética , Síndromes de Usher/genéticaRESUMO
Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
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Defeitos da Visão Cromática , Canais de Cátion Regulados por Nucleotídeos Cíclicos , Defeitos da Visão Cromática/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Humanos , Mutação , Células Fotorreceptoras Retinianas ConesRESUMO
PURPOSE: To report a case of typical delayed-onset hypoxic cortical blindness that occurred few days after resuscitation from drowning in a young male. METHODS: Neurological and ophthalmological examination were performed including optical coherence tomography (OCT), Goldmann perimetry, pattern electroretinogram (pERG), pattern and flash visual evoked potentials (pVEP and fVEP) and brain magnetic resonance imaging (MRI). RESULTS: At presentation, at day 12 post-hypoxic incident, best corrected visual acuity (BCVA) was reduced to hand motion OU with an abolished optokinetic nystagmus, a normal fundus and no relative afferent pupillary defect. Macular and peripapillary OCT were normal. Goldmann perimetry revealed bilateral centrocecal scotoma. pERG was normal while pVEPs were undetectable and fVEPs were abnormal with delayed, decreased and disorganized responses, without interhemispheric asymmetry. Brain MRI disclosed a bilateral cortical-subcortical occipital hypersignal with laminar necrosis and thus confirmed the diagnosis of delayed-onset hypoxic cortical blindness. Visual rehabilitation, including visual stimulation in the scotomatous areas, was associated with a dramatic and rapid visual improvement with a BCVA of 20/32 OU, an ability to read after 2 weeks (day 30 post-hypoxic incident), and a reduction in the size of the scotoma. CONCLUSION: Delayed-onset hypoxic cortical blindness is a rare presentation of cortical blindness that develops few days after a cerebral hypoxic stress. While initial presentation can be catastrophic, visual improvement may be spectacular and enhanced with visual rehabilitation.
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Cegueira Cortical , Eletrorretinografia , Cegueira/diagnóstico , Cegueira/etiologia , Cegueira Cortical/diagnóstico , Cegueira Cortical/etiologia , Eletrorretinografia/métodos , Potenciais Evocados Visuais , Humanos , Masculino , Escotoma/diagnóstico , Escotoma/etiologia , Tomografia de Coerência Óptica , Transtornos da Visão/diagnósticoRESUMO
Mutations in GPR179 are one of the most common causes of autosomal recessive complete congenital stationary night blindness (cCSNB). This retinal disease is characterized in patients by impaired dim and night vision, associated with other ocular symptoms, including high myopia. cCSNB is caused by a complete loss of signal transmission from photoreceptors to ON-bipolar cells. In this study, we hypothesized that the lack of Gpr179 and the subsequent impaired ON-pathway could lead to myopic features in a mouse model of cCSNB. Using ultra performance liquid chromatography, we show that adult Gpr179-/- mice have a significant decrease in both retinal dopamine and 3,4-dihydroxyphenylacetic acid, compared to Gpr179+/+ mice. This alteration of the dopaminergic system is thought to be correlated with an increased susceptibility to lens-induced myopia but does not affect the natural refractive development. Altogether, our data added a novel myopia model, which could be used to identify therapeutic interventions.
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Doenças Genéticas Ligadas ao Cromossomo X , Miopia , Cegueira Noturna , Camundongos , Animais , Eletrorretinografia/métodos , Cegueira Noturna/genética , Retina , Miopia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Receptores Acoplados a Proteínas G/genéticaRESUMO
Inherited retinal diseases (IRD) are a group of heterogeneous disorders, most of which lead to blindness with limited therapeutic options. Pathogenic variants in RBP4, coding for a major blood carrier of retinol, retinol-binding protein 4, are responsible for a peculiar form of IRD. The aim of this study was to investigate if retinal function of an RBP4-related IRD patient can be improved by retinol administration. Our patient presented a peculiar white-dot retinopathy, reminiscent of vitamin A deficient retinopathy. Using a customized next generation sequencing (NGS) IRD panel we discovered a novel loss-of-function homozygous pathogenic variant in RBP4: c.255G >A, p.(Trp85*). Western blotting revealed the absence of RBP4 protein in the patient's serum. Blood retinol levels were undetectable. The patient was put on a high-dose oral retinol regimen (50,000 UI twice a week). Subjective symptoms and retinal function markedly and sustainably improved at 5-months and 1-year follow-up. Here we show that this novel IRD case can be treated by oral retinol administration.
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Distrofias Retinianas , Vitamina A , Humanos , Retina/metabolismo , Distrofias Retinianas/tratamento farmacológico , Distrofias Retinianas/genética , Proteínas Plasmáticas de Ligação ao Retinol/genética , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Vitamina A/uso terapêuticoRESUMO
Variants in the X-linked retinitis pigmentosa GTPase regulator gene (RPGR) and, specifically, in its retinal opening reading frame-15 isoform (RPGRORF15) may cause rod-cone (RCD), cone, and cone-rod dystrophies (CDs and CRDs). While RPGR-related RCDs have been frequently evaluated, the characteristics and progression of RPGR-related CD/CRDs are largely unknown. Therefore, the goal of our work was to perform genotype-phenotype correlations specifically in RPGRORF15-related CD/CRDs. This retrospective longitudinal study included 34 index patients and two affected relatives with a molecular diagnosis of RPGR-related CD/CRDs. Patients were recruited at the "Quinze-Vingts" Hospital, Paris, France and screened for mutations in RPGRORF15 at the Institut de la Vision, Paris, France. We identified 29 distinct variants, of which 27 were truncating. All were located in the 3' half of the RPGRORF15 transcript. Twenty of them were novel. Fifteen subjects were affected by CD, the remaining had CRD. When analyzing the longitudinal data, a progressive decline in visual acuity (VA) was noted, with more than 60% of the patients reaching VA ≥ 1 LogMar in the best eye after the fifth decade of life. To our knowledge, this is the largest described study of a cohort of CD/CRD patients affected by RPGRORF15 variants. Longitudinal data showed a rapidly progressive disease, possibly locating an optimal window of intervention for future therapies in younger ages.
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Distrofias de Cones e Bastonetes , Proteínas do Olho , Retinose Pigmentar , Distrofias de Cones e Bastonetes/genética , Proteínas do Olho/genética , Genes Reguladores , Humanos , Estudos Longitudinais , Mutação , Linhagem , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Estudos RetrospectivosRESUMO
Objective: This article aims to describe a unique case of didanosine-induced retinal degeneration that was discovered 11 years after the drug withdrawal. Case report: The patient is a 42-year-old woman with a medical history of HIV and hepatitis C virus since 2004. She has been prescribed antiretroviral therapy since then. For the first seven years (2004-2011), the patient was prescribed a combination therapy consisting of didanosine, efavirenz, and lamivudine. The protocol was changed to atripla (efavirenz, emtricitabine, and tenofovir) from 2011 to 2021. Recently (October 2021-January 2021), the patient was prescribed eviplera (rilpivirin, emtricitabine, and tenofovir). In addition, her past medical history revealed Gougerot-Sjogren syndrome and rheumatoid arthritis. She was prescribed hydroxychloroquine (HCQ) (2009-2021) at a dose of 400 mg daily. She had no vision complaint. Results: During her routine HCQ screening at the eye clinic, University Hospital Bretonneau, Tours, France, the widefield colour fundus photograph showed well-defined symmetric mid-peripheral areas of chorioretinal atrophy sparing the posterior pole of both eyes. Furthermore, the widefield fundus autofluorescence illustrated mid-peripheral round well-demarcation hypoautofluorescent areas of chorioretinal atrophy of both eyes. Conversely, the macular optical coherence tomography (OCT) was normal. Many of her drugs are known to be associated with retinopathy such as HCQ, tenofovir, efavirenz, and didanosine. Because our data corroborate peripheral retinal damage rather than posterior pole damage, this case report is compatible with didanosine-induced retinopathy rather than HCQ, efavirenz, or tenofovir retinal toxicity. Conclusions: All HIV patients who are presently or were previously on didanosine therapy should have their fundus examined utilising widefield fundus autofluorescence and photography.
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Infecções por HIV , Degeneração Retiniana , Adulto , Atrofia , Doenças da Coroide , Didanosina/efeitos adversos , Emtricitabina/uso terapêutico , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Hidroxicloroquina/uso terapêutico , Degeneração Retiniana/induzido quimicamente , Tenofovir/efeitos adversos , Tomografia de Coerência Óptica/métodosRESUMO
Background and Objectives: Long-term hydroxychloroquine (HCQ) therapy can lead to retinal toxicity. Typically, it is characterized by a bull's eye maculopathy. More recently, a "pericentral" form of HCQ retinopathy that predominantly affects patients of Asian descent has been described. To our knowledge, this is the first reported case where such an asymmetry between the right and the left eye in the toxicity profile is observed. Case presentation: The patient presented with a 12-year exposure to HCQ at a daily dose of 4.35 mg/kg. She presented an inferior pericentral-only phenotype of HCQ toxicity on the right eye and a perifoveal-only toxicity on the left eye. Modest progression of toxicity was observed on both eyes over the seven years of follow-up, despite drug discontinuation. Conclusions: To our knowledge, this is the first time that two different phenotypes of HCQ-related retinopathy are found in the same patient, challenging our understanding of the pathophysiology of HCQ retinal toxicity.
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Antirreumáticos , Degeneração Macular , Doenças Retinianas , Antirreumáticos/toxicidade , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/tratamento farmacológico , Tomografia de Coerência ÓpticaRESUMO
Choroideremia is an X-linked inherited retinal disorder (IRD) characterized by the degeneration of retinal pigment epithelium, photoreceptors, choriocapillaris and choroid affecting males with variable phenotypes in female carriers. Unlike other IRD, characterized by a large clinical and genetic heterogeneity, choroideremia shows a specific phenotype with causative mutations in only one gene, CHM. Ongoing gene replacement trials raise further interests in this disorder. We describe here the clinical and genetic data from a French cohort of 45 families, 25 of which carry novel variants, in the context of 822 previously reported choroideremia families. Most of the variants represent loss-of-function mutations with eleven families having large (i.e. ≥6 kb) genomic deletions, 18 small insertions, deletions or insertion deletions, six showing nonsense variants, eight splice site variants and two missense variants likely to affect splicing. Similarly, 822 previously published families carry mostly loss-of-function variants. Recurrent variants are observed worldwide, some of which linked to a common ancestor, others arisen independently in specific CHM regions prone to mutations. Since all exons of CHM may harbor variants, Sanger sequencing combined with quantitative polymerase chain reaction or multiplex ligation-dependent probe amplification experiments are efficient to achieve the molecular diagnosis in patients with typical choroideremia features.
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Proteínas Adaptadoras de Transdução de Sinal , Coroideremia , Proteínas Adaptadoras de Transdução de Sinal/genética , Coroideremia/diagnóstico , Coroideremia/genética , Coroideremia/terapia , Éxons , Feminino , Heterozigoto , Humanos , Masculino , MutaçãoRESUMO
Cyclic nucleotide-gated channel ß1 (CNGB1) encodes the 240-kDa ß subunit of the rod photoreceptor cyclic nucleotide-gated ion channel. Disease-causing sequence variants in CNGB1 lead to autosomal recessive rod-cone dystrophy/retinitis pigmentosa (RP). We herein present a comprehensive review and analysis of all previously reported CNGB1 sequence variants, and add 22 novel variants, thereby enlarging the spectrum to 84 variants in total, including 24 missense variants (two of which may also affect splicing), 21 nonsense, 19 splicing defects (7 at noncanonical positions), 10 small deletions, 1 small insertion, 1 small insertion-deletion, 7 small duplications, and 1 gross deletion. According to the American College of Medical Genetics and Genomics classification criteria, 59 variants were considered pathogenic or likely pathogenic and 25 were variants of uncertain significance. In addition, we provide further phenotypic data from 34 CNGB1-related RP cases, which, overall, are in line with previous findings suggesting that this form of RP has long-term retention of useful central vision despite the early onset of night blindness, which is valuable for patient counseling, but also has implications for it being considered a priority target for gene therapy trials.
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Distrofias de Cones e Bastonetes/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Estudos de Coortes , Distrofias de Cones e Bastonetes/classificação , Distrofias de Cones e Bastonetes/epidemiologia , Distrofias de Cones e Bastonetes/patologia , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , MutaçãoRESUMO
Rod-cone dystrophy (RCD), also called retinitis pigmentosa, is characterized by rod followed by cone photoreceptor degeneration, leading to gradual visual loss. Mutations in over 65 genes have been associated with non-syndromic RCD explaining 60% to 70% of cases, with novel gene defects possibly accounting for the unsolved cases. Homozygosity mapping and whole-exome sequencing applied to a case of autosomal recessive non-syndromic RCD from a consanguineous union identified a homozygous variant in WDR34. Mutations in WDR34 have been previously associated with severe ciliopathy syndromes possibly associated with a retinal dystrophy. This is the first report of a homozygous mutation in WDR34 associated with non-syndromic RCD.
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Proteínas de Transporte/genética , Distrofias de Cones e Bastonetes/genética , Adulto , Estudos de Associação Genética , Humanos , Masculino , Linhagem , Repetições WD40RESUMO
Sensorineural hearing loss (SNHL) is characteristic of Usher syndrome type 2 (USH2), but less is known about SNHL in nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) and olfaction in USH2A-associated retinal degeneration. The Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) is a natural history study that enrolled 127 participants, 80 with USH2 and 47 with ARRP. Hearing was measured by pure-tone thresholds and word recognition scores, and olfaction by the University of Pennsylvania Smell Identification Test (UPSIT). SNHL was moderate in 72% of USH2 participants and severe or profound in 25%, while 9% of ARRP participants had moderate adult-onset SNHL. Pure-tone thresholds worsened with age in ARRP but not in USH2 participants. The degree of SNHL was not associated with other participant characteristics in either USH2 or ARRP. Median pure-tone thresholds in ARRP participants were significantly higher than the normative population (p < 0.001). Among 14 USH2 participants reporting newborn hearing screening results, 7 reported passing. Among RUSH2A participants, 7% had mild microsmia and 5% had moderate or severe microsmia. Their mean (±SD) UPSIT score was 35 (±3), similar to healthy controls (34 [±3]; p = 0.39). Olfaction differed by country (p = 0.02), but was not significantly associated with clinical diagnosis, age, gender, race/ethnicity, smoking status, visual measures, or hearing. Hearing loss in USH2A-related USH2 did not progress with age. ARRP patients had higher pure-tone thresholds than normal. Newborn hearing screening did not identify all USH2A-related hearing loss. Olfaction was not significantly worse than normal in participants with USH2A-related retinal degeneration.
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Proteínas da Matriz Extracelular/genética , Predisposição Genética para Doença , Perda Auditiva Neurossensorial/genética , Retinose Pigmentar/genética , Síndromes de Usher/genética , Adolescente , Adulto , Idade de Início , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/patologia , Olfato/genética , Síndromes de Usher/diagnóstico , Síndromes de Usher/patologia , Adulto JovemRESUMO
PURPOSE: To reappraise the presentation and the course of ITM2B-related retinal dystrophy and give further insights into ITM2B expression in the retina. METHODS: The clinical data of nine subjects with ITM2B-related retinal dystrophy were retrospectively reviewed. The genetic mutation was assessed for its influence on splicing in cultured fibroblasts. The cellular expression of ITM2B within the inner retina was investigated in wild-type mice through mRNA in situ hybridization. RESULTS: All patients complained of decreased vision and mild photophobia around their twenties-thirties. The peculiar feature was the hyperreflective material on optical coherence tomography within the inner retina and the central outer nuclear layer with thinning of the retinal nerve fiber layer. Although retinal imaging revealed very mild or no changes over the years, the visual acuity slowly decreased with about one Early Treatment Diabetic Retinopathy Study letter per year. Finally, full-field electroretinography showed a mildly progressive inner retinal and cone dysfunction. ITM2B mRNA is expressed in all cellular types of the inner retina. Disease mechanism most likely involves mutant protein misfolding and/or modified protein interaction rather than misplicing. CONCLUSION: ITM2B-related retinal dystrophy is a peculiar, rare, slowly progressive retinal degeneration. Functional examinations (full-field electroretinography and visual acuity) seem more accurate in monitoring the progression in these patients because imaging tends to be stable over the years.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Distrofias Retinianas/genética , Idoso , Animais , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Hibridização In Situ , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Imagem Óptica , Fenótipo , RNA Mensageiro/genética , Retina/fisiopatologia , Distrofias Retinianas/diagnóstico por imagem , Distrofias Retinianas/fisiopatologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
Mutations in GPR179 lead to autosomal recessive complete congenital stationary night blindness (cCSNB). This condition represents a signal transmission defect from the photoreceptors to the ON-bipolar cells. To confirm the phenotype, better understand the pathogenic mechanism in vivo, and provide a model for therapeutic approaches, a Gpr179 knock-out mouse model was genetically and functionally characterized. We confirmed that the insertion of a neo/lac Z cassette in intron 1 of Gpr179 disrupts the same gene. Spectral domain optical coherence tomography reveals no obvious retinal structure abnormalities. Gpr179 knock-out mice exhibit a so-called no-b-wave (nob) phenotype with severely reduced b-wave amplitudes in the electroretinogram. Optomotor tests reveal decreased optomotor responses under scotopic conditions. Consistent with the genetic disruption of Gpr179, GPR179 is absent at the dendritic tips of ON-bipolar cells. While proteins of the same signal transmission cascade (GRM6, LRIT3, and TRPM1) are correctly localized, other proteins (RGS7, RGS11, and GNB5) known to regulate GRM6 are absent at the dendritic tips of ON-bipolar cells. These results add a new model of cCSNB, which is important to better understand the role of GPR179, its implication in patients with cCSNB, and its use for the development of therapies.