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Sterile alpha motif domain containing 7 (SAMD7) is a component of the Polycomb repressive complex 1, which inhibits transcription of many genes, including those activated by the transcription factor Cone-Rod Homeobox (CRX). Here we report bi-allelic mutations in SAMD7 as a cause of autosomal-recessive macular dystrophy with or without cone dysfunction. Four of these mutations affect splicing, while another mutation is a missense variant that alters the repressive effect of SAMD7 on CRX-dependent promoter activity, as shown by in vitro assays. Immunostaining of human retinal sections revealed that SAMD7 is localized in the nuclei of both rods and cones, as well as in those of cells belonging to the inner nuclear layer. These results place SAMD7 as a gene crucial for human retinal function and demonstrate a significant difference in the role of SAMD7 between the human and the mouse retina.
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Anomalías del Ojo , Degeneración Macular , Ratones , Animales , Humanos , Transactivadores/genética , Proteínas de Homeodominio/genética , Retina , Mutación/genética , Degeneración Macular/genéticaRESUMEN
PURPOSE: Gyrate atrophy of the choroid and retina (GACR) is an autosomal recessive inherited metabolic disorder (IMD) characterised by progressive retinal degeneration, leading to severe visual impairment. The rapid developments in ophthalmic genetic therapies warrant knowledge on clinical phenotype of eligible diseases such as GACR to define future therapeutic parameters in clinical trials. METHODS: Retrospective chart analysis was performed in nineteen patients. Data were analysed using IBM SPSS Statistics version 28.0.1.1. RESULTS: Nineteen patients were included with a mean age of 32.6 years (range 8-58). Mean age at onset of ophthalmic symptoms was 7.9 years (range 3-16). Median logMAR of visual acuity at inclusion was 0.26 (range -0.18-3.00). Mean age at cataract surgery was 28.8 years (n = 11 patients). Mean spherical equivalent of the refractive error was -8.96 (range -20.87 to -2.25). Cystoid maculopathy was present in 68% of patients, with a loss of integrity of the foveal ellipsoid zone (EZ) in 24/38 eyes. Of the 14 patients treated with dietary protein restriction, the four patients who started the diet before age 10 showed most benefit. CONCLUSION: This study demonstrates the severe ophthalmic disease course associated with GACR, as well as possible benefit of early dietary treatment. In addition to visual loss, patients experience severe myopia, early-onset cataract, and CME. There is a loss of foveal EZ integrity at a young age, emphasising the need for early diagnosis enabling current and future therapeutic interventions.
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Objective. The introduction of advanced endoscopic systems, such as the Storz Image1S and the Olympus Endoeye, heralds a new era of 3-dimensional (3D) visualization. The aim of this report is to provide a comprehensive overview of the neurophysiology of 3D view, its relevance in videoscopy, and to quantify the benefit of the new 3D technologies for both rigid and articulated instruments. Method. Sixteen medical students without any laparoscopic experience were trained each for a total of 27 hours. Proficiency scores were determined for rigid and articulated instruments under 2D and 3D visualization conditions. Results. A reduction in execution time of 14%, 28%, and 36% was seen for the rigid instruments, the da Vinci, and Steerable instruments, respectively. A reduction in errors of 84%, 92%, and 87% was seen for the rigid instruments, the da Vinci, and Steerable instruments, respectively. Conclusion. 3D visualization greatly augments endoscopic procedures. The advanced endoscopic systems employed in the recent study caused no visual fatigue or discomfort. The benefit of 3D was most distinct with articulated instruments.
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Astenopía/etiología , Educación de Pregrado en Medicina/métodos , Imagenología Tridimensional/instrumentación , Laparoscopía/instrumentación , Errores Médicos/estadística & datos numéricos , Instrumentos Quirúrgicos , Bélgica , Competencia Clínica , Evaluación Educacional , Diseño de Equipo , Femenino , Humanos , Masculino , Tempo Operativo , Estudiantes de Medicina , Análisis y Desempeño de Tareas , Adulto JovenRESUMEN
BACKGROUND: 5' untranslated regions (5'UTRs) are essential modulators of protein translation. Predicting the impact of 5'UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5'UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs). METHODS: We performed an isoform-level re-analysis of retinal RNA-seq data to identify the protein-coding transcripts of 378 IRD genes with highest expression in retina. We evaluated the coverage of their 5'UTRs by different whole exome sequencing (WES) kits. The selected 5'UTRs were analyzed in whole genome sequencing (WGS) and WES data from IRD sub-cohorts from the 100,000 Genomes Project (n = 2397 WGS) and an in-house database (n = 1682 WES), respectively. Identified variants were annotated for 5'UTR-relevant features and classified into seven categories based on their predicted functional consequence. We developed a variant prioritization strategy by integrating population frequency, specific criteria for each category, and family and phenotypic data. A selection of candidate variants underwent functional validation using diverse approaches. RESULTS: Isoform-level re-quantification of retinal gene expression revealed 76 IRD genes with a non-canonical retina-enriched isoform, of which 20 display a fully distinct 5'UTR compared to that of their canonical isoform. Depending on the probe design, 3-20% of IRD genes have 5'UTRs fully captured by WES. After analyzing these regions in both cohorts, we prioritized 11 (likely) pathogenic variants in 10 genes (ARL3, MERTK, NDP, NMNAT1, NPHP4, PAX6, PRPF31, PRPF4, RDH12, RD3), of which 7 were novel. Functional analyses further supported the pathogenicity of three variants. Mis-splicing was demonstrated for the PRPF31:c.-9+1G>T variant. The MERTK:c.-125G>A variant, overlapping a transcriptional start site, was shown to significantly reduce both luciferase mRNA levels and activity. The RDH12:c.-123C>T variant was found in cis with the hypomorphic RDH12:c.701G>A (p.Arg234His) variant in 11 patients. This 5'UTR variant, predicted to introduce an upstream open reading frame, was shown to result in reduced RDH12 protein but unaltered mRNA levels. CONCLUSIONS: This study demonstrates the importance of 5'UTR variants implicated in IRDs and provides a systematic approach for 5'UTR annotation and validation that is applicable to other inherited diseases.
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Nicotinamida-Nucleótido Adenililtransferasa , Enfermedades de la Retina , Humanos , Regiones no Traducidas 5' , Tirosina Quinasa c-Mer , Retina , Enfermedades de la Retina/genética , Isoformas de Proteínas , Oxidorreductasas de AlcoholRESUMEN
BACKGROUND/AAIMS: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression. METHODS: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated. RESULTS: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively. CONCLUSIONS: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia.
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Objective: To describe a cohort of paediatric patients who underwent unilateral or bilateral lens extractions at Ghent University hospital using the Dutch Ophthalmic Research Center (D.O.R.C.) ultra-short 27G vitrectomy system. Methods: Retrospective analysis of the medical and surgical records of all children that underwent lens extraction between September 2016 and September 2020 using the D.O.R.C. ultra-short 27G vitrectomy system. Results: Seventy-two eyes of 52 patients were included. The most important aetiologies in this study were of secondary (25.5%), developmental (13.7%), or genetic (13.7%) nature. No definitive cause could be established in more than a quarter of cases (27.5%) despite extensive work-up, them being deemed idiopathic. The remainder of cases (19.6%) was not assigned a final aetiologic designation at the time of the study due to contradicting or missing diagnostic data. This study could not identify any cataract cases related to infection or trauma. Surgical complications rate was 61.1% of which posterior capsule opacification was the most frequent with a rate of 25%. A significant short-term postoperative best-corrected visual acuity gain (≤ -0.2 LogMAR) was observed in 60.5% of eyes for which usable acuity data were available (n = 38). Conclusion: Many different instruments and techniques have been described and used in the context of paediatric lens extractions, each with its advantages and disadvantages. This study illustrates that an ultra-short 27G vitrectomy system can be used to perform paediatric lens extractions with good surgical outcomes. Further studies and comparative trials are needed to ascertain this further.
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BACKGROUND: Congenital Stationary Night Blindness (CSNB) constitutes a group of non-progressive retinal disorders characterized by disturbances in scotopic vision and/or by a delay in adaptation to darkness, as well as by low visual acuity, myopia, nystagmus, and strabismus. Color vision and fundus appearance tend to be normal. To date, several CACNA1F gene variants have been linked to a CSNB phenotype but only few reports have focused on the optic nerve in this disease. MATERIALS AND METHODS: Twelve patients underwent standard ophthalmological and genetic evaluation including spectral domain optical coherence tomography (SD-OCT), full-field electroretinography (ffERG), kinetic perimetry, fundus photography, magnetic resonance imaging (MRI), and next-generation sequencing (NGS). Bilateral thinning of the peripapillary nerve fiber layer (pRNFL) and the ganglion cell complex (GCC) supported involvement of the optic nerves. MRI, when available, was assessed for gross intracranial optic pathway abnormalities. RESULTS: All patients were shown to carry pathogenic variants in the CACNA1F gene, and all showed signs of optic nerve involvement. All patients showed a certain degree of myopic refractive error. Low average pRNFL thickness was evident in all patients. In three of them, pRNFL thickness was evaluated longitudinally and was proven to be stable over time. MRI imaging was unremarkable in all cases. CONCLUSION: Our data support the hypothesis that CACNA1F could be related to early-onset or congenital optic nerve involvement without any signs of a progressive optic neuropathy. Even though additional data from larger cohorts and longer follow-up periods are needed to further support and confirm our findings, there is a clear significance to our findings in the preparation for future CACNA1F gene therapy trials.