RESUMEN
Purpose: Recent studies have shown that the retinal pigment epithelium (RPE) relies on fatty acid oxidation (FAO) for energy, however, its role in overall retinal health is unknown. The only FAO disorder that presents with chorioretinopathy is long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). Studying the molecular mechanisms can lead to new treatments for patients and elucidate the role of FAO in the RPE. This paper characterizes the chorioretinopathy progression in a recently reported LCHADD mouse model. Methods: Visual assessments, such as optokinetic tracking and fundus imaging, were performed in wildtype (WT) and LCHADD mice at 3, 6, 10, and 12 months of age. Retinal morphology was analyzed in 12-month retinal cross-sections using hematoxylin and eosin (H&E), RPE65, CD68, and TUNEL staining, whereas RPE structure was assessed using transmission electron microscopy (TEM). Acylcarnitine profiles were measured in isolated RPE/sclera samples to determine if FAO was blocked. Bulk RNA-sequencing of 12 month old male WT mice and LCHADD RPE/sclera samples assessed gene expression changes. Results: LCHADD RPE/sclera samples had a 5- to 7-fold increase in long-chain hydroxyacylcarnitines compared to WT, suggesting an impaired LCHAD step in long-chain FAO. LCHADD mice have progressively decreased visual performance and increased RPE degeneration starting at 6 months. LCHADD RPE have an altered structure and a two-fold increase in macrophages in the subretinal space. Finally, LCHADD RPE/sclera have differentially expressed genes compared to WT, including downregulation of genes important for RPE function and angiogenesis. Conclusions: Overall, this LCHADD mouse model recapitulates early-stage chorioretinopathy seen in patients with LCHADD and is a useful model for studying LCHADD chorioretinopathy.
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Modelos Animales de Enfermedad , Epitelio Pigmentado de la Retina , Animales , Ratones , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Ratones Endogámicos C57BL , 3-Hidroxiacil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Enfermedades de la Coroides/genética , Enfermedades de la Coroides/metabolismo , Masculino , Enfermedades de la Retina/genética , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/fisiopatología , Microscopía Electrónica de TransmisiónRESUMEN
INTRODUCTION: Alagille syndrome (AGS) is a genetic disease with multisystemic affection, including ocular manifestations. Recently, a high frequency of posterior segment findings, including macular changes, has been reported. This publication aims to report an unusual finding of macular atrophy and a focal choroidal excavation in a patient with JAG1 related AGS. METHODS: Case report. RESULTS: This publication describes an atypical presentation of focal choroidal excavation (FCE) and unilateral macular atrophy in a 7-year-old male with Alagille syndrome (AGS). Genetic analysis revealed a pathogenic variant in the JAG1 gene. Ophthalmological examination and imaging findings demonstrated characteristic ocular manifestations of AGS, including posterior embryotoxon, chorioretinal atrophy, and thinning of the choroid. CONCLUSION: The presence of FCE in AGS is uncommon, and the underlying mechanisms remain unclear. Further exploration of similar cases is necessary to better understand the evolution and visual prognosis in patients with AGS and FCE.
This case report highlights the presence of focal choroidal excavation and unilateral macular atrophy in a patient with Alagille syndrome. The genetic analysis identified a pathogenic variant in the JAG1 gene.
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Síndrome de Alagille , Proteína Jagged-1 , Humanos , Síndrome de Alagille/genética , Síndrome de Alagille/complicaciones , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/patología , Proteína Jagged-1/genética , Masculino , Niño , Tomografía de Coherencia Óptica , Enfermedades de la Coroides/genética , Enfermedades de la Coroides/diagnóstico , Angiografía con Fluoresceína , Agudeza Visual/fisiología , Atrofia , Mácula Lútea/patología , Mácula Lútea/anomalías , Coroides/patología , Coroides/anomalíasRESUMEN
BACKGROUND: Microcephaly and chorioretinopathy (MCCRP) is a rare autosomal recessive (AR) disorder characterized by microcephaly, developmental delay, chorioretinopathy, and visual impairment. We characterized the long-term phenotype of an additional patient with MCCRP associated with TUBCGP4 pathogenic variants and analysed previously reported cases in the literature. MATERIALS AND METHODS: Analysis of clinical and genetic data of a patient with TUBGCP4-related MCCRP followed for more than 19 years and literature search for previously reported patients with TUBCGP4 variants using PubMed, Scopus, and Google Scholar. RESULTS: Molecular diagnosis using exome sequencing demonstrated two TUBCGP4 variants in trans: c.1669C>T (p.Arg557*) and c.1746 G>T (p.Leu582=). Clinical characteristics included microcephaly, microphthalmia, punched-out chorioretinal lesions, vision impairment, nystagmus, Tetralogy of Fallot and neurodevelopmental delay. Another six previously reported cases of TUBCGP4-related MCCRP were identified. Their clinical and genetic characteristics are compared. CONCLUSIONS: TUBCGP4-related microcephaly and chorioretinopathy, is a rare autosomal recessive neuro-ophthalmic disorder. Clinical characteristics in our proband have remained stable for two decades. The pathophysiology of this syndrome is not yet fully understood.
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Enfermedades de la Coroides , Microcefalia , Enfermedades de la Retina , Humanos , Microcefalia/genética , Microcefalia/patología , Enfermedades de la Retina/genética , Enfermedades de la Coroides/genética , Ojo , Familia , Fenotipo , Proteínas Asociadas a Microtúbulos/genéticaRESUMEN
Purpose: The purpose of this study was to evaluate the pathological involvement of erythropoietin (EPO) in experimental choroidal neovascularization (CNV) and its association with neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) in the Chinese population. Methods: Treatment effect of recombinant EPO protein were assessed by human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation, and ex vivo choroid-sprouting ability. The effect of intravitreal injection of Epo siRNA against neovascularization was evaluated in the laser-induced CNV mouse model. In addition, the association of EPO variants with neovascular AMD and PCV was determined. Results: Exogenous supplementation of EPO significantly enhanced the migration and tube formation of HUVECs and promoted ex vivo choroid sprouting in mouse retinal pigment epithelium (RPE)-choroid-sclera complex culture. In the experimental CNV mouse model, Epo expression was found to be significantly upregulated by 3.5-folds in RPE-choroid-sclera complex at day 10 after laser induction as compared to the baseline. Immunofluorescence analysis showed that Epo was mainly expressed around the vascular endothelial cells in the RPE-choroid-sclera complex. Intravitreal injection of siRNA targeting Epo reduced 40% Epo expression and 40% CNV lesion areas as compared to the scramble control. However, EPO variants were not associated with neovascular AMD nor PCV in the Chinese population. Conclusions: This study revealed the promotion of human endothelial cell tube formation in vitro and choroid sprouting ex vivo by EPO, and the reduction of laser-induced CNV in vivo by Epo RNA interference. Translational Relevance: Targeting EPO could be a potential additional treatment for CNV-related diseases.
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Enfermedades de la Coroides , Neovascularización Coroidal , Eritropoyetina , Degeneración Macular Húmeda , Inhibidores de la Angiogénesis , Animales , Enfermedades de la Coroides/genética , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/genética , Eritropoyetina/genética , Eritropoyetina/metabolismo , Eritropoyetina/farmacología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Rayos Láser , Ratones , Interferencia de ARN , ARN Interferente Pequeño/genética , Agudeza Visual , Degeneración Macular Húmeda/genéticaRESUMEN
Autosomal recessive microcephaly and chorioretinopathy (MCCRP) is a neurodevelopmental disorder characterized by delayed psychomotor development, growth retardation with dwarfism, and ocular abnormalities, and its occurrence has been found to be closely related to variants of the gene encoding centrosomes. However, the association between centrosomal duplication defects and the etiology of microcephaly syndromes is poorly understood. It is well known that polo-like kinase 4 (PLK4) is a key regulator of centriole duplication, and the abnormalities of centrosomal function caused by its protein variation need to be further explored in the pathogenesis of microcephaly. In our study, we found that a patient with microcephaly and chorioretinopathy harbored compound heterozygous missense variants NM_014264.4: c.2221C > T (p.Gln741*) and NM_014264.4: c.2062 T > C (p.Tyr688His) in the PLK4 gene. Overexpression experiments of the variant PLK4 proteins then showed that the G741 variant rather than the T688H variant had lost centrosomal amplification ability, and the G741 variant but not the T688H variant induced centrosomal replication disorder, which further inhibited cell proliferation, cycle division and cytoskeleton morphology in HeLa cells. Moreover, the overexpression of the two variant proteins had inconsistent effects on the target protein PLK4 by western blot analysis, also indicating that T688H variant overexpression is not functionally equivalent to WT-PLK4 overexpression. Therefore, all data support the idea that the PLK4 mutation induces centriolar duplication disorder and reduces the efficiency of mitosis inducing cell death or cell proliferation in the etiology of microcephaly disorder.
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Centrosoma/metabolismo , Enfermedades de la Coroides/genética , Enfermedades Hereditarias del Ojo/genética , Microcefalia/genética , Proteínas Serina-Treonina Quinasas/genética , Enfermedades de la Retina/genética , Ciclo Celular , Replicación del ADN , Células HeLa , Humanos , Mutación Missense , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
PURPOSE: Waardenburg syndrome (WS) is a rare condition characterized by six main features. It has been previously observed that WS is also associated with hypopigmentation of the choroid through multimodal imaging. To our knowledge, this is the first report of using swept-source optical coherence tomography angiography (OCTA) on a patient with known WS. METHODS: Report of a single case. The swept-source OCT images were captured using Topcon DRI OCT Triton (Topcon, Inc, Tokyo, Japan), whereas swept-source OCTA images were captured by Optovue AngioVue (Optovue, Inc, Fremont, CA) using DualTrack Motion Correction Technology. RESULTS: In this case, OCTA demonstrated evidence of normal vasculature of all layers (superficial, deep, and choricocapillaris), a normal foveal avascular zone measuring 0.267 mm2 in the right eye and 0.307 mm2 in the left eye, and a normal capillary density measuring 49.8% in the right eye and 52.6% in the left eye. CONCLUSION: There are many conditions that may mimic the hypopigmentation of the choroid associated with WS; it has been documented that these similar conditions such as choroidal nevus, choroidal melanoma, and Vogt-Koyanagi-Harada syndrome all demonstrated abnormal OCTA findings. Unlike these conditions, our patient with WS had unremarkable OCTA findings.
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Enfermedades de la Coroides/diagnóstico , Hipopigmentación/diagnóstico , Epitelio Pigmentado de la Retina/patología , Síndrome de Waardenburg/diagnóstico , Adulto , Enfermedades de la Coroides/genética , Angiografía por Tomografía Computarizada , Femenino , Angiografía con Fluoresceína , Humanos , Hipopigmentación/genética , Tomografía de Coherencia Óptica , Síndrome de Waardenburg/genéticaRESUMEN
Background Microcephaly and chorioretinopathy (MCCRP) is a rare neuro-ophthalmologic disorder that causes microcephaly and chorioretinopathy. In a recessive inheritance pattern, there are three types: MCCRP1; MCCRP2 and MCCRP3. MCCRP3 results from pathogenic variants in the tubulin-gamma complex-associated protein 4 (TUBGCP4) gene.Materials and Methods This is a case report of a patient with a molecular diagnosis defined by mutations in the TUBGCP4 gene. Segregation analyses were carried out.Results The molecular investigation found two heterozygous variants c.1380 G > A (p.Trp460*) a novel nonsense variant, and c.1746 G > T (p Leu582=) a synonymous variant in TUBGCP4. The clinical phenotype was characterized by microcephaly, microphthalmia, chorioretinopathy, a punched-out retinal appearance, dysmorphic facial features, decreased visual acuity, and learning difficulties. The clinical features were similar to those described previously in children with MCCRP3. The proband also had additional features including centripetal obesity, stretch marks, acanthosis nigricans, scoliosis, and hypercholesterolemia. These other features could be part of a ciliopathy syndrome.Conclusions MCCRP2 caused by pathogenic variants in PLK4 is well established as a ciliopathy disease. The role of TUBGCP4 is not well established in the cilium physiology. MCCRP3 may be part of the ciliopathy spectrum.
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Enfermedades de la Coroides/patología , Microcefalia/patología , Proteínas Asociadas a Microtúbulos/genética , Mutación , Enfermedades de la Retina/patología , Niño , Enfermedades de la Coroides/genética , Femenino , Humanos , Microcefalia/genética , Fenotipo , Enfermedades de la Retina/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: Polypoidal choroidal vasculopathy (PCV) is a retinal disorder characterized by the presence of aneurismal polypoidal lesions in the choroidal vasculature. A single nucleotide polymorphism (SNP) is a common genetic variant which may be associated with the disease. This study is to investigate the association of HERPUD1 (rs2217332) gene with PCV in the Indian population and develop an automated system for genotype and phenotype correlation using fundus images and machine learning methods. METHODS: A cohort of 54 PCV patients and 120 control subjects were recruited for the study. Genotyping of SNP (HERPUD1, rs2217332) was performed by following polymerase chain reaction and direct sequencing method. Statistical association of SNP to PCV was determined using chi-square analysis. The acquired GG and AG images were preprocessed using an adaptive histogram. 19 and 18 texture features were extracted from the images in the PCV naïve cases and PCV patients on treatment, respectively. Student's independent t-test was then employed for the selection of significant features, which were input to the ensemble tree for automated classification. Leave-one-out validation was used to evaluate the system. RESULTS: HERPUD1 rs2217332 SNP is significantly associated in PCV patients compared to control (P = 0.0296, odds ratio [OD] = 2.297, 95% confidence interval [CI] = 1.087-4.856) in the Indian population. High F1 and precision values of 85.71%, 86.84% and 85.71%, 93.75% were achieved in the pre and post- treatment phases, respectively. CONCLUSION: Our results suggest that the HERPUD1 polymorphism is associated in PCV patients. Based on our analysis, it may be possible to predict the genotype and disease status of PCV patients using fundus images in assistance with a machine learning algorithm.
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Enfermedades de la Coroides/diagnóstico , Enfermedades de la Coroides/genética , Diagnóstico por Computador , Genotipo , Fenotipo , Retina/fisiopatología , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/genética , Estudios de Cohortes , HumanosRESUMEN
BACKGROUND: Peters plus syndrome (PPS) is a combination of congenital Peters anomaly and systemic abnormalities. It is inherited most commonly in an autosomal recessive pattern with homozygous B3GLCT mutations. Ocular findings consist predominantly anterior segment abnormalities without posterior segment involvement. CASE PRESENTATION: In this presentation, we report a case of PPS with homozygous pathogenic variant in B3GLCT who presented with classic anterior segment findings, systemic abnormalities, as well as atypical bilateral chorioretinal atrophy. The chorioretinal findings were characterized with spectral-domain optical coherence tomography. CONCLUSIONS: Our report expands the phenotypic descriptions of PPS by characterizing posterior segment findings.
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Enfermedades de la Coroides/genética , Labio Leporino/genética , Córnea/anomalías , Galactosiltransferasas/genética , Glucosiltransferasas/genética , Trastornos del Crecimiento/genética , Deformidades Congénitas de las Extremidades/genética , Mutación/genética , Enfermedades de la Retina/genética , Segmento Anterior del Ojo/anomalías , Enfermedades de la Coroides/diagnóstico , Labio Leporino/diagnóstico , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Angiografía con Fluoresceína , Trastornos del Crecimiento/diagnóstico , Humanos , Lactante , Deformidades Congénitas de las Extremidades/diagnóstico , Masculino , Enfermedades de la Retina/diagnóstico , Tomografía de Coherencia ÓpticaRESUMEN
Best vitelliform macular dystrophy (BD), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and the autosomal recessive bestrophinopathy (ARB), together known as the bestrophinopathies, are caused by mutations in the bestrophin-1 (BEST1) gene affecting anion transport through the plasma membrane of the retinal pigment epithelium (RPE). To date, while no treatment exists a better understanding of BEST1-related pathogenesis may help to define therapeutic targets. Here, we systematically characterize functional consequences of mutant BEST1 in thirteen RPE patient cell lines differentiated from human induced pluripotent stem cells (hiPSCs). Both BD and ARB hiPSC-RPEs display a strong reduction of BEST1-mediated anion transport function compared to control, while ADVIRC mutations trigger an increased anion permeability suggesting a stabilized open state condition of channel gating. Furthermore, BD and ARB hiPSC-RPEs differ by the degree of mutant protein turnover and by the site of subcellular protein quality control with adverse effects on lysosomal pH only in the BD-related cell lines. The latter finding is consistent with an altered processing of catalytic enzymes in the lysosomes. The present study provides a deeper insight into distinct molecular mechanisms of the three bestrophinopathies facilitating functional categorization of the more than 300 known BEST1 mutations that result into the distinct retinal phenotypes.
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Bestrofinas/genética , Bestrofinas/metabolismo , Enfermedades Hereditarias del Ojo/genética , Mutación , Fenotipo , Enfermedades de la Retina/genética , Línea Celular , Enfermedades de la Coroides/genética , Enfermedades de la Coroides/metabolismo , Enfermedades de la Coroides/patología , Enfermedades Hereditarias del Ojo/metabolismo , Enfermedades Hereditarias del Ojo/patología , Genes Recesivos , Predisposición Genética a la Enfermedad/genética , Homeostasis , Humanos , Concentración de Iones de Hidrógeno , Células Madre Pluripotentes Inducidas , Retina/metabolismo , Retina/patología , Degeneración Retiniana/genética , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología , Epitelio Pigmentado de la Retina/metabolismo , Distrofia Macular ViteliformeRESUMEN
BACKGROUND: To report the occurrence of choroidal hypoplasia in the Australian Kelpie breed in Poland, the affected dogs testing positive for the Collie Eye Anomaly NHEJ1 gene mutation. CASE PRESENTATIONS: Choroidal hypoplasia (CH) was initially diagnosed in a young female Australian Kelpie presented for routine ophthalmological examination prior to breeding. Indirect ophthalmoscopy revealed tigroid fundi bilaterally with areas of abnormally arranged choroidal vasculature temporal to the optic disc. These lesions had the appearance of the choroidal hypoplasia diagnostic for Collie Eye Anomaly, a genetically determined disease seen most commonly in Collie types. The DNA based test for the NHEJ1 gene mutation that is confirmatory for Collie Eye Anomaly proved the dog to be homozygous for this mutation. Twenty one other related dogs were subsequently examined genetically, the dam proving to be affected and eight others were shown to be carriers. CONCLUSIONS: This report demonstrates that Collie Eye Anomaly is present in a Polish bred Australian Kelpie line and as such breeders in this country and those importing dogs or semen internationally should be aware of other possible cases.
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Enfermedades de la Coroides/veterinaria , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Enfermedades de los Perros/congénito , Animales , Enfermedades de la Coroides/genética , Perros , Femenino , Predisposición Genética a la Enfermedad , Masculino , Mutación , Linaje , Polonia/epidemiologíaRESUMEN
Small molecule pharmacological inhibition of dominant human genetic disease is a feasible treatment that does not rely on the development of individual, patient-specific gene therapy vectors. However, the consequences of protein inhibition as a clinical therapeutic are not well-studied. In advance of human therapeutic trials for CAPN5 vitreoretinopathy, genetic inactivation can be used to infer the effect of protein inhibition in vivo. We created a photoreceptor-specific knockout (KO) mouse for Capn5 and compared the retinal phenotype to both wild-type and an existing Capn5 KO mouse model. In humans, CAPN5 loss-of-function (LOF) gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes. Ocular examination of the retina of Capn5 KO mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 LOF CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these LOF variants were nearby known disease-causing variants within the proteolytic core and in regions of high homology between human CAPN5 and 150 homologs, yet the LOF of CAPN5 was tolerated as opposed to gain-of-function disease-causing variants. These results indicate that localized inhibition of CAPN5 is a viable strategy for hyperactivating disease alleles.
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Calpaína/genética , Enfermedades de la Coroides/genética , Enfermedades Hereditarias del Ojo/genética , Mutación , Degeneración Retiniana/genética , Tamoxifeno/farmacología , Animales , Calpaína/química , Calpaína/metabolismo , Modelos Animales de Enfermedad , Femenino , Técnicas de Inactivación de Genes , Silenciador del Gen , Humanos , Masculino , Ratones , Modelos Moleculares , Células Fotorreceptoras de Vertebrados/metabolismoAsunto(s)
Enfermedades de la Coroides/complicaciones , Coroides/irrigación sanguínea , Degeneración Macular/complicaciones , Pólipos/complicaciones , Retina/patología , Inhibidor Tisular de Metaloproteinasa-3/genética , Anciano , Enfermedades de la Coroides/diagnóstico , Enfermedades de la Coroides/genética , Femenino , Angiografía con Fluoresceína/métodos , Fondo de Ojo , Humanos , Degeneración Macular/diagnóstico , Degeneración Macular/genética , Masculino , Persona de Mediana Edad , Fenotipo , Pólipos/diagnóstico , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Tomografía de Coherencia Óptica/métodosRESUMEN
Adenosine diphosphate (ADP)-ribosylation factor-like 2 (ARL2) protein participates in a broad range of cellular processes and acts as a mediator for mutant ARL2BP in cilium-associated retinitis pigmentosa and for mutant HRG4 in mitochondria-related photoreceptor degeneration. However, mutant ARL2 has not been linked to any human disease so far. Here, we identified a de novo variant in ARL2 (c.44G > T, p.R15L) in a Chinese pedigree with MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome through whole-exome sequencing and co-segregation analysis. Co-immunoprecipitation assay and immunoblotting confirmed that the mutant ARL2 protein showed a 62% lower binding affinity for HRG4 while a merely 18% lower binding affinity for ARL2BP. Immunofluorescence images of ARL2 and HRG4 co-localizing with cytochrome c in HeLa cells described their relationship with mitochondria. Further analyses of the mitochondrial respiratory chain and adenosine triphosphate production showed significant abnormalities under an ARL2-mutant condition. Finally, we generated transgenic mice to test the pathogenicity of this variant and observed retinal degeneration complicated with microcornea and cataract that were similar to those in our patients. In conclusion, we uncover ARL2 as a novel candidate gene for MRCS syndrome and suggest a mitochondria-related mechanism of the first ARL2 variant through site-directed mutagenesis studies.
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Enfermedades de la Coroides/diagnóstico , Enfermedades de la Coroides/genética , Secuenciación del Exoma , Enfermedades Hereditarias del Ojo/diagnóstico , Enfermedades Hereditarias del Ojo/genética , Proteínas de Unión al GTP/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Fenotipo , Degeneración Retiniana/diagnóstico , Degeneración Retiniana/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Adulto , Alelos , Sustitución de Aminoácidos , Animales , Proteínas Portadoras , Niño , Consanguinidad , Modelos Animales de Enfermedad , Femenino , Proteínas de Unión al GTP/química , Humanos , Masculino , Ratones , Ratones Transgénicos , Modelos Moleculares , Mutación , Linaje , Unión Proteica , Conformación Proteica , Relación Estructura-ActividadRESUMEN
PURPOSE: Autosomal dominant vitreoretinochoroidopathy is an extremely rare disease, which belongs to the BEST1-related disease spectrum. METHODS: Report of five patients with an initial diagnosis of atypical rod-cone dystrophy, for whom autosomal dominant vitreoretinochoroidopathy was retrospectively diagnosed on genetic results using targeted next-generation sequencing. Each patient had a comprehensive ophthalmic examination including multimodal retinal imaging and functional evaluation. RESULTS: Visual acuity ranged from <20/800 to 20/25. Two patients had narrowed angle with history of acute angle-closure glaucoma for one patient. Full-field electroretinogram showed severe reduction of both scotopic and photopic responses for 3/5 patients. Electrooculogram could be performed for one of the two patients with moderate alterations of full-field electroretinogram. It revealed severe light rise abnormalities with decreased Arden ratio (125% right eye, 145% left eye) in keeping with generalized severe dysfunction of the retinal pigment epithelium. On fundoscopy, the pathognomonic circumferential hyperpigmented band of the peripheral retina was totally absent in two patients. CONCLUSION: This report highlights the high phenotypic variability of autosomal dominant vitreoretinochoroidopathy, which may be misdiagnosed, especially in advanced forms with severe generalized photoreceptor dysfunction mimicking retinitis pigmentosa. Targeted next-generation sequencing can contribute to the proper clinical diagnosis, especially in case of atypical phenotypic features of autosomal dominant vitreoretinochoroidopathy.
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Enfermedades de la Coroides/diagnóstico , Enfermedades Hereditarias del Ojo/diagnóstico , Proteínas del Ojo/genética , Pruebas Genéticas/métodos , Degeneración Retiniana/diagnóstico , Campos Visuales , Anciano , Enfermedades de la Coroides/genética , Enfermedades de la Coroides/metabolismo , Diagnóstico Diferencial , Electrorretinografía , Enfermedades Hereditarias del Ojo/genética , Enfermedades Hereditarias del Ojo/metabolismo , Proteínas del Ojo/metabolismo , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Fondo de Ojo , Humanos , Persona de Mediana Edad , Oftalmoscopía , Linaje , Degeneración Retiniana/genética , Degeneración Retiniana/metabolismo , Estudios Retrospectivos , Tomografía de Coherencia ÓpticaRESUMEN
BACKGROUND: To report a 68-year-old female with an autosomal-dominant vitreoretinochoroidopathy (ADVIRC) phenotype associated with a subretinal hemorrhage (SRH) and novel BEST1 pathogenic variation p.Met571Thr. MATERIALS AND METHODS: The patient was assessed by fundus photography, fluorescence and indocyanine green angiography, spectral-domain optical coherence tomography, photopic and scotopic electroretinogram (ERG), and electrooculogram (EOG). Whole-exome and Sanger sequencing of the patient's and selected family members' DNA was performed. Ophthalmoscopic examinations were also performed on six patient's relatives. RESULTS: The patient presented moderate vitreous and SRH in the left eye. A distinct, annular hyperpigmented band was present in both eyes. Vitrectomy improved visual acuity, and the SRH gradually regressed without recurrence. Preserved macular function was shown by optical coherence tomography (OCT). Genetic analysis identified a novel heterozygous mutation, resulting in p.Met571Thr in BEST1. No mutations were observed in a panel of other eye disease genes, suggesting that this pathogenic variation in BEST1 is associated with an ADVIRC phenotype. No other evaluated family member had the variant or the fundus findings. CONCLUSIONS: We present a patient with a novel p.Met571Thr pathogenic variation associated with an ADVIRC phenotype. SRH is a unique finding in ADVIRC patients and may correspond to peripheral exudative hemorrhagic chorioretinopathy. The BEST1 pathogenic variation p.Met571Thr might be the likely cause of ADVIRC in this patient. However, further study is necessary to determine whether this mutation is causative.
Asunto(s)
Bestrofinas/genética , Enfermedades de la Coroides/genética , Enfermedades Hereditarias del Ojo/genética , Mutación Missense , Degeneración Retiniana/genética , Hemorragia Retiniana/genética , Anciano , Enfermedades de la Coroides/diagnóstico , Colorantes/administración & dosificación , Electrorretinografía , Enfermedades Hereditarias del Ojo/diagnóstico , Femenino , Angiografía con Fluoresceína , Genes Dominantes , Heterocigoto , Humanos , Verde de Indocianina/administración & dosificación , Oftalmoscopía , Linaje , Fenotipo , Degeneración Retiniana/diagnóstico , Hemorragia Retiniana/diagnóstico , Tomografía de Coherencia Óptica , Agudeza Visual , Secuenciación del ExomaRESUMEN
Purpose: This study aims to quantify the concentration of apolipoprotein A1 (APOA1) and retinol binding protein (RBP4) expressed in the vitreous humors of patients with rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD), rhegmatogenous retinal detachment (RRD), and idiopathic epimacular membrane (IEM). This study also aims to investigate the potential role of APOA1 and RBP4 as biomarkers of RRDCD. Methods: Enzyme-linked immunosorbent assay (ELISA) kits were used to obtain levels of APOA1 and RBP4 from the vitreous humor samples of 76 primary patients. These patients included 23 patients with RRDCD, 28 patients with RRD, and 24 patients with IEM. All patients were undergoing planned pars plana vitrectomy. The differences between the concentrations of the molecular biomarkers among different patient groups were analyzed using the Mann-Whitney U-test for nonparametric values and independent samples t-test or one-way ANOVA analysis for parametric data. The relationship between the molecular biomarkers, grades of proliferative vitreoretinopathy (PVR), and quadrants of retinal detachment were analyzed using nonparametric Spearman's rank correlation analysis. Results: The vitreous concentrations of APOA1 and RBP4 were statistically significantly higher in the RRDCD group compared to the RRD and IEM groups. Patients with severe PVR demonstrated a higher concentration of APOA1 and RBP4 compared to those with mild PVR, but this finding was not statistically significant. There was a statistically significant positive correlation between APOA1 and RBP4 in the RRDCD and RRD groups. Nonparametric Spearman's rank correlation analysis revealed that levels of APOA1 and RBP4 increased statistically significantly with an increasing number of detached retinal quadrants in the RRDCD and RRD groups. Conclusions: The findings of this study allude to the potential of APOA1 and RBP4 as specific biomarkers of RRDCD. The findings of this study may contribute to increased understanding regarding the role of APOA1 and RBP4 in RRDCD.
Asunto(s)
Apolipoproteína A-I/genética , Enfermedades de la Coroides/genética , Enfermedades Hereditarias del Ojo/genética , Degeneración Macular/genética , Desprendimiento de Retina/genética , Proteínas Plasmáticas de Unión al Retinol/genética , Anciano , Apolipoproteína A-I/metabolismo , Biomarcadores/metabolismo , Coroides/metabolismo , Coroides/patología , Coroides/cirugía , Enfermedades de la Coroides/diagnóstico , Enfermedades de la Coroides/metabolismo , Enfermedades de la Coroides/cirugía , Enfermedades Hereditarias del Ojo/diagnóstico , Enfermedades Hereditarias del Ojo/metabolismo , Enfermedades Hereditarias del Ojo/cirugía , Femenino , Expresión Génica , Humanos , Degeneración Macular/diagnóstico , Degeneración Macular/metabolismo , Degeneración Macular/cirugía , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Retina/metabolismo , Retina/patología , Retina/cirugía , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/metabolismo , Desprendimiento de Retina/cirugía , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Índice de Severidad de la Enfermedad , Vitrectomía , Cuerpo Vítreo/metabolismo , Cuerpo Vítreo/patología , Cuerpo Vítreo/cirugíaRESUMEN
OBJECTIVE: To describe the frequency of the nonhomologous end-joining factor 1 (NHEJ1) mutation and the compliance between clinical and genetic diagnosis of choroidal hypoplasia (CH) in a group of Norwegian Border Collies. ANIMALS STUDIED: Border collie puppies in the age from 5 to 8 weeks. MATERIAL AND METHODS: Puppies included in the study had a complete ophthalmological examination. All findings were recorded, and an ECVO scheme form was issued for each puppy. DNA samples were achieved from buccal swabs. Genetic typing was performed for the 7.8-kb deletion in the gene encoding NHEJ1. Dogs with none, one, or two copies of the mutated allele were classified as free, carriers, and affected, respectively. RESULTS: 103 Border Collie puppies from 16 litters, 52 females and 51 males, were included in the study. Ages ranged from 5.1 to 8.9 weeks. One puppy had clinical findings consistent with CH and optic nerve coloboma compatible with the diagnosis Collie Eye Anomaly (CEA). Findings on ophthalmological examination of the remaining puppies were within normal limits. On genetic testing, 85 puppies were clear of the mutation in the NHEJ1 gene, 17 puppies were carriers, and one puppy was genetically affected. CONCLUSIONS: A good compliance between the clinical diagnosis and the genetic test results was found in all of the puppies examined. The allele frequency of the mutation was 6.3%.