ABSTRACT
BACKGROUND@#Age-related macular degeneration (AMD) is the leading cause of vision loss worldwide. However, the mechanisms involved in the development and progression of AMD are poorly delineated. We aimed to explore the critical genes involved in the progression of AMD.@*METHODS@#The differentially expressed genes (DEGs) in AMD retinal pigment epithelial (RPE)/choroid tissues were identified using the microarray datasets GSE99248 and GSE125564, which were downloaded from the gene expression omnibus database. The overlapping DEGs from the two datasets were screened to identify DEG-related biological pathways using gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The hub genes were identified from these DEGs through protein-protein interaction network analyses. The expression levels of hub genes were evaluated by quantitative real-time polymerase chain reaction following the induction of senescence in ARPE-19 with FK866. Following the identification of AMD-related key genes, the potential small molecule compounds targeting the key genes were predicted by PharmacoDB. Finally, a microRNA-gene interaction network was constructed.@*RESULTS@#Microarray analyses identified 174 DEGs in the AMD RPE compared to the healthy RPE samples. These DEGs were primarily enriched in the pathways involved in the regulation of DNA replication, cell cycle, and proteasome-mediated protein polyubiquitination. Among the top ten hub genes, HSP90AA1, CHEK1, PSMA4, PSMD4, and PSMD8 were upregulated in the senescent ARPE-19 cells. Additionally, the drugs targeting HSP90AA1, CHEK1, and PSMA4 were identified. We hypothesize that Hsa-miR-16-5p might target four out of the five key DEGs in the AMD RPE.@*CONCLUSIONS@#Based on our findings, HSP90AA1 is likely to be a central gene controlling the DNA replication and proteasome-mediated polyubiquitination during the RPE senescence observed in the progression of AMD. Targeting HSP90AA1, CHEK1, PSMA4, PSMD4, and/or PSMD8 genes through specific miRNAs or small molecules might potentially alleviate the progression of AMD through attenuating RPE senescence.
Subject(s)
Humans , DNA Replication , Gene Expression Profiling , Gene Ontology , Macular Degeneration/genetics , Proteasome Endopeptidase ComplexABSTRACT
ABSTRACT - This report presents three patients diagnosed with macular dystrophies with variants in PRPH2. Peripherin-2, the protein of this gene, is important in the morphogenesis and stabilization of the photoreceptor outer segment. Peripherin-2 deficiencies cause cellular apoptosis. Moreover, pathogenic variants in PRPH2 are associated with various diseases, such as pattern, butterfly-shaped pattern, central areolar, adult-onset vitelliform macular, and cone-rod dystrophies as well as retinitis pigmentosa, retinitis punctata albescens, Leber congenital amaurosis, fundus flavimaculatus, and Stargardt disease.
RESUMO - Este relato apresenta três pacientes com diagnóstico de distrofias maculares com mutações no PRPH2. Periferina 2, a proteína deste gene, é importante na morfogênese e estabilização do segmento externo dos fotorreceptores. Deficiências de periferina 2 causam apoptose celular. Além disso, variantes patogênicas no PRPH2 estão relacionadas a diferentes doenças, como distrofia padrão, distrofia padrão em asa de borboleta, distrofia central areolar, distrofia viteliforme do adulto, retinose pigmentar, distrofia de cones e bastonetes, retinite punctata albscens, amaurose congênita de Leber, fundus flavimaculatus e doença de Stargardt.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Retinal Dystrophies/genetics , Retinal Dystrophies/diagnostic imaging , Peripherins/genetics , Macular Degeneration/genetics , Macular Degeneration/diagnostic imaging , Mutation , Fluorescein Angiography/methods , Tomography, Optical Coherence/methods , Retinal Dystrophies/pathology , Macular Degeneration/pathologyABSTRACT
ABSTRACT We report on a case of two sisters, daughters of consanguineous parents, presenting with a similar condition of low visual acuity associated with retinal dystrophy in both eyes associated with alopecia and bone alterations or syndactyly.
RESUMO Relatamos um caso de duas irmãs, filhas de pais consanguíneos, apresentando uma condição semelhante de baixa acuidade visual associado à distrofia retiniana em ambos os olhos associado à alopecia e alterações ósseas ou sindactilia.
Subject(s)
Humans , Female , Child , Adolescent , Ectodermal Dysplasia/genetics , Ectodermal Dysplasia/diagnostic imaging , Hand Deformities, Congenital/genetics , Hand Deformities, Congenital/diagnostic imaging , Consanguinity , Macular Degeneration/congenital , Siblings , Macular Degeneration/genetics , Macular Degeneration/diagnostic imagingABSTRACT
ABSTRACT Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder characterized by sparse scalp hair caused by hair follicle abnormalities as well as progressive retinal degeneration leading to blindness in the second or third decade of life. It is associated with mutations of the cadherin 3 (CDH3) gene, which result in abnormal expression of P-cadherin. Mutations in CDH3 are related to ectodermal dysplasia, ectrodactyly, and macular dystrophy. In this report, we describe an 11-year-old Iranian boy born with a missing left index fingernail and sparse scalp hair who later displayed macular pigmentary changes. Genetic testing of the CDH3 gene revealed a homozygous gene variant at exon 6 (640A>T). This novel in-frame mutation converts a lysine to a premature stop codon, altering synthesis of P-cadherin on chromosome 16q22.
RESUMO Hipotricose com distrofia macular juvenil (HDMJ) é uma doença autossômica recessiva rara caracterizada por rarefação capilar por alteração nos folículos pilosos e degeneracão progressiva da retina levando a cegueira na segunda e terceira década de vida. Associada a mutações no gene CDH3, resultando em expressão anormal de P-caderina. Mutações no gene CDH3 estão relacionados à displasia ectodérmica, ectrodactilia e distrofia macular. Neste relato descrevemos um menino Iraniano de 11 anos de idade, com ausência da unha na mão esquerda e rarefação capilar desde o nascimento, e que posteriormente apresentou alterações pigmentares maculares. Teste genético do gene CDH3 revelou uma variação homozigótica no exon 6 (640A>T). Essa mutação in-frame troca uma lisina por um codon de parada prematura, alterando a síntese da proteína P-caderina no cromossomo 16q22.
Subject(s)
Humans , Male , Child , Cadherins/genetics , Corneal Dystrophies, Hereditary/genetics , Hypotrichosis/genetics , Macular Degeneration/genetics , Iran , MutationABSTRACT
ABSTRACTPurpose:To evaluate the association between the VEGF-C936T polymorphism and serum vascular endothelial growth factor (VEGF) levels, lifestyle, and demographic parameters in patients with age-related macular degeneration (AMD).Methods:A total of 183 individuals were enrolled in the present study, including 88 patients with AMD receiving clinical and pharmacological treatment (study group, SG) and 95 individuals without AMD as controls (control group, CG). The presence of the VEGF-C936T polymorphism and serum VEGF levels were determined using polymerase chain reaction/restriction fragment length polymorphism and enzyme-linked immunosorbent assay, respectively. Significance was set at P<0.05 for all statistical analyses.Results:The homozygous wild-type genotype (CC) and the C allele were predominant in both groups (P=0.934 and P=0.938, respectively). Serum VEGF levels (assessed in 57% and 31% of patients in the SG and CG, respectively) were comparable between groups (SG, 307.9 ± 223.6 pg/mL; CG, 305.1 ± 212.3 pg/mL; P=0.955). A significantly higher prevalence of smoking (44% vs 25%; P=0.01) and hypertension (66% vs 48%; P=0.025) was observed in the SG than in the CG. The distribution of alcohol consumption and dyslipidemia was similar between groups (P>0.05).Conclusions:In the present study group of Brazilian patients, the VEGF-C936T polymorphism was not found to be associated with age-related macular degeneration. However, smoking and systemic arterial hypertension (SAH) were found to be potential independent risk factors for the development of age-related macular degeneration. Comparable serum VEGF levels in both study groups may reflect the efficacy of pharmacological treatment of AMD.
RESUMOObjetivo:Avaliar a associação entre o polimorfismo VEGF-C936T, níveis séricos de VEGF (vascular endothelial growth factor), hábitos de vida e antecedentes pessoais em pacientes com degeneração macular relacionada à idade (DRMI).Métodos:Foram estudados 183 indivíduos: 88 pacientes com degeneração macular relacionada à idade, em tratamento clínico e medicamentoso (Grupo Estudo - GE) e 95 indivíduos sem sinais clínicos da doença (Grupo Controle - GC). O polimorfismo VEGF-C936T e os níveis séricos de VEGF foram analisados por PCR/RFLP e ELISA, respectivamente. Admitiu-se nível de significância para P<0.05.Resultados:O genótipo homozigoto selvagem (CC) prevaleceu em ambos os grupos (P=0,934), assim como o alelo C (P=0,938). Os níveis séricos de VEGF, analisados em 57% de SG e em 31% de CG, apresentaram valores semelhantes entre pacientes e controles (GE=307,9 ± 223,6 pg/mL; GC=305,1 ± 212,3 pg/mL; P=0,955). Notou-se maior frequência de tabagismo (44%) e hipertensão arterial sistêmica (66%) em GE versus GC (25%; 48%; P=0,01; P=0,025, respectivamente). A distribuição de etilismo e dislipidemia foi semelhante entre os grupos (P>0,05).Conclusões:Em nosso estudo com pacientes brasileiros, o polimorfismo VEGF-C936T não se associa com degeneração macular relacionada à idade, por outro lado, tabagismo e HAS são potencialmente fatores de risco independentes para a doença, enquanto níveis de VEGF semelhantes em ambos os grupos podem refletir o sucesso do tratamento farmacológico.
Subject(s)
Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Life Style , Macular Degeneration/genetics , Polymorphism, Single Nucleotide , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor A/genetics , Alcohol Drinking/adverse effects , Brazil , Case-Control Studies , Dyslipidemias/complications , Enzyme-Linked Immunosorbent Assay , Genetic Association Studies , Hypertension/complications , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Risk Factors , Smoking/adverse effects , Tomography, Optical CoherenceABSTRACT
Age-related macular degeneration [AMD] is one of the leading causes of visual loss among people aged 65 yr and older. The pathophysiology of AMD is poorly understood. The purpose of this study was to evaluate the relationship between serum lipid concentrations and age-related macular degeneration. In this case-control study, total cholesterol [TCH], low density lipoprotein [LDL], high density lipoprotein [HDL] and triglyceride [TG] of 32 patients with AMD were compared with 32 subjects without AMD that were matched for age. Data were analyzed using Independent t and Chi-Square Tests. TCH, LDL, and TG serum concentrations were significantly higher in AMD patients compared with control group [P<0.001, P<0.001 and P<0.017 respectively]. There was no difference in HDL concentration between two groups [P=0.781]. High level of total cholesterol, TG and LDL were associated with increased risk of AMD. Results of this study suggest further research to better understand the underlying biological mechanisms of AMD related to serum cholesterol
Subject(s)
Humans , Male , Female , Cholesterol, LDL/blood , Cholesterol, HDL/blood , Macular Degeneration/genetics , Risk Factors , Triglycerides/blood , Case-Control Studies , Chi-Square DistributionABSTRACT
This case report describes the presence of bilateral macular atrophy in a patient with Alport syndrome and compares this finding with literature. At fundoscopy, there was a discrete circumscribed macular thinning showing intense retinal pigment epithelium color and the presence of whitish circular retinal lesions ("dots" and "flecks") at nasal mid periphery of both eyes. Optical coherence tomography showed bilateral partial atrophy of the neurosensory retina in the macula, with a greater extent in the temporal region. This case describes a rare ophthalmological finding in Alport syndrome and important to be recognized for a precise diagnosis as well as for determining visual prognosis.
Este relato de caso descreve a presença de atrofia macular bilateral em uma paciente com síndrome de Alport e compara este achado com a literatura. Ao exame fundoscópico, havia discreto afinamento macular circunscrito demonstrando a coloração intensa do epitélio pigmentado da retina e a presença de lesões retinianas circulares esbranquiçadas ("dots" e "flecks") na média periferia nasal em ambos os olhos. A tomografia de coerência óptica identificou atrofia parcial da retina neurossensorial bilateral na mácula, com maior extensão na área temporal. O caso descreve uma alteração oftalmológica rara da síndrome de Alport e de importante reconhecimento para precisar o diagnóstico e também para determinar o prognóstico visual.
Subject(s)
Female , Humans , Middle Aged , Macular Degeneration/genetics , Nephritis, Hereditary/complications , Retina/abnormalities , Macular Degeneration/diagnosis , Tomography, Optical Coherence , Visual AcuityABSTRACT
Age-related macular degeneration (AMD) is a degenerative disorder that affects the central retina and involves the Bruch's membrane, the retinal pigment epithelium and the photoreceptors. Recent studies have shown that polymorphisms of the CFH, LOC387715 and VEGF genes are associated with AMD. Herein, we review the literature to analyze the association between the main genetic polymorphisms and the response to the existing therapeutic modalities. Patients with CFH high-risk alleles show a poorer response to preventive treatment of AMD with antioxidants and zinc.The association between genetic polymorphisms and response to photodynamic therapy and antiangiogenic drugs, however, is controversial until now.
A degeneração macular relacionada à idade (DMRI) é uma doença degenerativa que afeta a retina central e envolve a membrana de Bruch, o epitélio pigmentar da retina e os fotorreceptores. Estudos recentes têm mostrado que polimorfismos dos genes CFH, LOC387715 e VEGF estão associados com a DMRI. Neste trabalho, é feita uma revisão da literatura para análise da associação entre os principais polimorfismos genéticos e a resposta às diferentes modalidades terapêuticas existentes. Observa-se que os pacientes portadores dos alelos de risco do gene CFH apresentam uma pior resposta ao tratamento preventivo da DMRI com antioxidantes e zinco. Já a associação entre o polimorfismo genético e a resposta à terapia fotodinâmica e às drogas antiangiogênicas é, até o momento, controversa.
Subject(s)
Humans , Polymorphism, Genetic/genetics , Genetic Predisposition to Disease , Angiogenesis Inhibitors/therapeutic use , Macular Degeneration/genetics , Macular Degeneration/drug therapy , Antioxidants/therapeutic use , Photochemotherapy/methods , Zinc/therapeutic use , Aging/genetics , Photosensitizing Agents/therapeutic use , Complement Factor H/genetics , Choroidal Neovascularization/genetics , Vascular Endothelial Growth Factor A/genetics , Bevacizumab/therapeutic use , Ranibizumab/therapeutic use , Genotype , Macular DegenerationABSTRACT
PURPOSE: To investigate whether the G6721T polymorphism (rs.7003908) of the non-homologous end-joining DNA repair XRCC7 gene contributes to the development of exudative age-related macular degeneration (ARMD). METHODS: The present case-control study consisted of 111 patients with exudative ARMD and 112 sex frequency-matched healthy controls that were randomly selected from unrelated volunteers in the same clinic. Genotypes were determined by the Restriction Fragment Length Polymorphism (PCR-RFLP) based method. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for ARMD risk associated with polymorphism of XRCC7. In all analysis the GG genotype was considered to be the reference genotype. RESULTS: There was no significant association between genotypes of XRCC7 and susceptibility to ARMD. Considering the significant difference in age distribution between cases and controls, age was used as a covariate in further analysis. After ORs were adjusted for age, the same result was observed. In the next step we stratified our subjects into outdoor and indoor groups according to their job titles. The outdoor and indoor patients were occupationally exposed to sunlight and not exposed to sunlight, respectively. Our present study showed that among indoor subjects there was no association between XRCC7 polymorphism and susceptibility to ARMD. However, among outdoor subjects, the GT + TT genotypes compared to the GG genotype increased the risk of ARMD (OR, 3.13; 95% CI, 1.04-9.39; p = 0.042). CONCLUSIONS: Our study revealed that the T allele of the G6721T polymorphism of XRCC7 increased the risk of ARMD among outdoor subjects.
Subject(s)
Aged , Female , Humans , Male , Middle Aged , DNA/genetics , DNA-Activated Protein Kinase/genetics , Environmental Exposure , Exudates and Transudates , Follow-Up Studies , Genetic Predisposition to Disease , Genotype , Macular Degeneration/genetics , Nuclear Proteins/genetics , Polymerase Chain Reaction , Polymorphism, Genetic , Retrospective Studies , Risk FactorsABSTRACT
Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Although the etiology of AMD remains largely unknown, numerous studies have suggested that both genes and environmental risk factors significantly influence the risk of developing AMD. Recently, single nucleotide polymorphisms, DNA sequence variations found within the complement factor H (CFH) gene, have been found to be strongly associated with the development of AMD. Several other genes have had at least one positive association finding and deserve further exploration. The purpose of this review is to provide an extensive report of the current data of AMD genetics and the contribution of this knowledge helps to the better understanding of its pathophysiology.
A degeneração macular relacionada à idade (DMRI) é a causa mais frequente de cegueira irreversível em idosos em países desenvolvidos. Apesar da etiologia da DMRI ainda permanecer desconhecida, numerosos estudos tem sugerido que tanto fatores genéticos quanto ambientais influenciam significativamente no risco do desenvolvimento da doença. Recentemente, polimorfismos de base única, variações na sequência de DNA encontradas no gene fator H do complemento (CFH), tem sido fortemente associado com o desenvolvimento da DMRI. Muitos outros genes tiveram ao menos um resultado positivo para esta associação e merecem estudos posteriores. O objetivo dessa revisão é proporcionar descrição atual dos dados publicados.
Subject(s)
Humans , Macular Degeneration/genetics , Disease Progression , Gene Frequency , Genetic Predisposition to Disease/genetics , Polymorphism, Genetic , Risk FactorsABSTRACT
Colágeno XVIII, uma proteoglicana, é um componente das membranas basais (MBs). Existem três isoformas distintas que diferem apenas na região N-terminal, mas que apresentam um padrão específico de expressão nos diferentes tecidos e durante o desenvolvimento. A clivagem da região C-terminal produz endostatina, um inibidor de angiogênese. Na sua região N-terminal, há um motivo "frizzled'', o qual parece estar envolvido com a sinalização de Wnt. Mutações no gene COL18A1 causam a síndrome de Knobloch (SK), uma condição de herança autossômica recessiva caracterizada por degeneração vítreo - retiniana, degeneração de mácula e encefalocele occipital. Esta revisão discute o efeito tanto de alelos raros como polimórficos no fenótipo, mostrando que deficiência de uma das isoformas de colágeno XVIII é suficiente para causar SK e que alelos nulos causando deficiência de todas as isoformas de colágeno XVIII estão associadas a alterações oculares mais graves. Esta revisão, além de ilustrar a importância funcional do colágeno XVIII no desenvolvimento do olho e na manutenção de sua estrutura, também mostra que esta proteína tem um papel funcional importante em outros tecidos e órgão, como no sistema nervoso central e rim.
Subject(s)
Humans , Collagen Type XVIII/genetics , Encephalocele/genetics , Eye Diseases, Hereditary/genetics , Mutation/genetics , Phenotype , Retinal Degeneration/genetics , Alleles , Genotype , Macular Degeneration/genetics , Protein Isoforms/genetics , SyndromeABSTRACT
Este trabalho apresentou um caso clássico de rara Sindrome de Walker-Warburg, estudada nos departamentos de Oftalmologia e Neurologia infantil do Hospital das Clínicas da Faculdade de Medicina da Universidade de Säo Paulo, ressaltando-se os aspectos oftalmológicos, neurológicos e musculares característicos dessa doença. O diagnóstico precoce é possível, contribuíndo para a maior sobrevida dos pacientes
Subject(s)
Female , Infant , Macular Degeneration/genetics , Electroretinography , Retinal DegenerationSubject(s)
Humans , Middle Aged , Age Factors , Alleles , Blindness/etiology , Blindness/genetics , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 6/genetics , Macular Degeneration/etiology , Macular Degeneration/genetics , Genes, Dominant , Genes, Recessive , Mutation , Risk FactorsSubject(s)
Humans , Genetics, Medical , Sex Chromosome Aberrations/diagnosis , Sex Chromosome Aberrations/epidemiology , Sex Chromosome Aberrations/genetics , Sex Chromosome Aberrations/pathology , Sex Chromosome Aberrations/physiopathology , Macular Degeneration/etiology , Macular Degeneration/geneticsABSTRACT
Se trata de cuatro (4) pacientes, producto de padres consanguíneos, quienes al hallazgo oftalmológico se encontró disminución de la agudeza visual de 20/200 o menos, lesión atrófica en el área macular y múltiples manchas blanco-amarillentas en la periferia de la retina simétricas y bilaterales, que nos permitió determinar que se trata de una enfermedad de Stargardt
Subject(s)
Adolescent , Adult , Humans , Retina/pathology , Retinal Diseases/genetics , Retinal Diseases/pathology , Fundus Oculi , Macula Lutea/pathology , Macular Degeneration/geneticsABSTRACT
Los cambios en el epitelio pigmentario y la membrana de Bruch son producidos por el envejecimiento, más, ciertos factores personales. Pors fortuna, en la degeneración macular senil no es esencial el envejecimiento, es decir, no tiene universalidad. No todos los viejos sufren degeneración macular senil, lo que subraya la importancia de los factores personales. Estudios comparativos entre personas con degeneración macular senil y pacientes controles de la misma edad, han demostrado que los que sufren degeneración macular senil tienen menos fuerza de prehensión en la mano, esta observación parecería indicar que los pacientes con degeneración macular senil son mas viejos que los otros, aunque sean de la misma edad. Los factores personales, sumados al envejecimiento, llevan a cambios en el epitelio pigmentario y en la menmbrana de Bruch que clínica y angiográficamente se traducen en la aparición de las drusas. A partir de este punto la enfermedad puede tomar varios cursos clínicos: a) Hacia la atrofia geográfica b) Al desprendimiento del epitelio pigmentario con todas las complicaciones que hemos descrito c) A una neovascularización. Es solamente en esta forma clínica donde el oftalmólogo tiene una posible terapéutica, siempre que actúe en forma diligente y oportuna. La ausencia o fracaso de la terapéutica puede dar lugar a una cicatriz disciforme
Subject(s)
Aged , Humans , Male , Female , Aged , Macular Degeneration/geneticsABSTRACT
Neste trabalho o estudo do ERP é aplicado a diversos casos de patologías maculares hereditárias. O ERP foi estudado quanto à morfologia e amplitude e os resultados encontrados correlacionados com outros exames electrofisiológicos