Assuntos
Câmara Anterior/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Oculares/secundário , Neoplasias Pulmonares/patologia , Inibidores da Angiogênese/administração & dosagem , Câmara Anterior/diagnóstico por imagem , Câmara Anterior/efeitos dos fármacos , Antineoplásicos Imunológicos/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Oculares/diagnóstico por imagem , Neoplasias Oculares/tratamento farmacológico , Humanos , Injeções Intraoculares , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Fotografação , Lâmpada de Fenda , Microscopia com Lâmpada de Fenda/instrumentação , Resultado do Tratamento , Carga TumoralRESUMO
PURPOSE: Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and mutations in known genes can only explain 5-6% of POAG. This study was conducted to identify novel POAG-causing genes and explore the pathogenesis of this disease. METHODS: Exome sequencing was performed in a Han Chinese cohort comprising 398 sporadic cases with POAG and 2010 controls, followed by replication studies by Sanger sequencing. A heterozygous Ramp2 knockout mouse model was generated for in vivo functional study. RESULTS: Using exome sequencing analysis and replication studies, we identified pathogenic variants in receptor activity-modifying protein 2 (RAMP2) within three genetically diverse populations (Han Chinese, German, and Indian). Six heterozygous RAMP2 pathogenic variants (Glu39Asp, Glu54Lys, Phe103Ser, Asn113Lysfs*10, Glu143Lys, and Ser171Arg) were identified among 16 of 4763 POAG patients, whereas no variants were detected in any exon of RAMP2 in 10,953 control individuals. Mutant RAMP2s aggregated in transfected cells and resulted in damage to the AM-RAMP2/CRLR-cAMP signaling pathway. Ablation of one Ramp2 allele led to cAMP reduction and retinal ganglion cell death in mice. CONCLUSION: This study demonstrated that disruption of RAMP2/CRLR-cAMP axis could cause POAG and identified a potential therapeutic intervention for POAG.
Assuntos
Glaucoma de Ângulo Aberto/genética , Proteína 2 Modificadora da Atividade de Receptores/genética , Animais , Povo Asiático , Células COS , Proteína Semelhante a Receptor de Calcitonina/genética , Proteína Semelhante a Receptor de Calcitonina/metabolismo , China , Chlorocebus aethiops , Estudos de Coortes , AMP Cíclico/genética , Predisposição Genética para Doença/genética , Glaucoma de Ângulo Aberto/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Proteína 2 Modificadora da Atividade de Receptores/metabolismo , Sequenciamento do Exoma/métodosRESUMO
BACKGROUND: To describe the use of anterior segment optical coherence tomography (OCT) in imaging intrableb morphology after trabeculectomy. METHODS: 14 post-trabeculectomy eyes from 11 primary open angle glaucoma and 3 primary angle closure glaucoma subjects were studied. The blebs were classified with reference to slit lamp morphology and bleb function. They included diffuse filtering (n = 7), cystic (n = 2), encapsulated (n = 2) and flattened (n = 3) bleb types. One eye in each patient was imaged with the Visante anterior segment OCT. A vertical scan line of 10 mm consisting of 512 A-scans was positioned at the centre of the bleb. The images were then analysed by built-in software. Intrableb morphologies and structures, including bleb wall thickness, subconjunctival fluid collections, suprascleral fluid space, scleral flap thickness, intrableb intensity (low, medium or high) and the route under the scleral flap were characterised and measured. RESULTS: Diffuse filtering blebs were found by subconjunctival fluid collections. Suprascleral fluid space and the route under the scleral flap were identified in four of the seven cases. Cystic blebs were composed of a large hyporeflective space with multiloculated fluid collections covered by a thin layer of conjunctiva. Encapsulated blebs had a thick bleb wall with high reflectivity and an enclosed fluid filled space. Flattened blebs demonstrated high scleral reflectivity and no bleb elevation. CONCLUSIONS: Visante anterior segment OCT can be used for bleb imaging. The different patterns of intrableb morphology identified by OCT were related to slit lamp appearance and bleb function. This information may be useful to study the different surgical outcomes and the process of wound healing in trabeculectomised eyes.