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Pesquisa : D08.811.277.656.300.760.210 [Categoria DeCS]
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[PMID]:28671664
[Au] Autor:Xue X; Wu J; Ricklin D; Forneris F; Di Crescenzio P; Schmidt CQ; Granneman J; Sharp TH; Lambris JD; Gros P
[Ad] Endereço:Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
[Ti] Título:Regulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses.
[So] Source:Nat Struct Mol Biol;24(8):643-651, 2017 Aug.
[Is] ISSN:1545-9985
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The complement system labels microbes and host debris for clearance. Degradation of surface-bound C3b is pivotal to direct immune responses and protect host cells. How the serine protease factor I (FI), assisted by regulators, cleaves either two or three distant peptide bonds in the CUB domain of C3b remains unclear. We present a crystal structure of C3b in complex with FI and regulator factor H (FH; domains 1-4 with 19-20). FI binds C3b-FH between FH domains 2 and 3 and a reoriented C3b C-terminal domain and docks onto the first scissile bond, while stabilizing its catalytic domain for proteolytic activity. One cleavage in C3b does not affect its overall structure, whereas two cleavages unfold CUB and dislodge the thioester-containing domain (TED), affecting binding of regulators and thereby determining the number of cleavages. These data explain how FI generates late-stage opsonins iC3b or C3dg in a context-dependent manner, to react to foreign, danger or healthy self signals.
[Mh] Termos MeSH primário: Complemento C3b/química
Complemento C3b/metabolismo
Fator H do Complemento/química
Fator H do Complemento/metabolismo
Fator I do Complemento/química
Fator I do Complemento/metabolismo
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Seres Humanos
Modelos Moleculares
Ligação Proteica
Conformação Proteica
Proteólise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
80295-43-8 (Complement C3b); 80295-65-4 (Complement Factor H); EC 3.4.21.45 (Complement Factor I)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1038/nsmb.3427


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[PMID]:28637873
[Au] Autor:Kerr H; Wong E; Makou E; Yang Y; Marchbank K; Kavanagh D; Richards A; Herbert AP; Barlow PN
[Ad] Endereço:From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom.
[Ti] Título:Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface-selective regulation of complement activation.
[So] Source:J Biol Chem;292(32):13345-13360, 2017 Aug 11.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Spontaneous activation enables the complement system to respond very rapidly to diverse threats. This activation is efficiently suppressed by complement factor H (CFH) on self-surfaces but not on foreign surfaces. The surface selectivity of CFH, a soluble protein containing 20 complement-control protein modules (CCPs 1-20), may be compromised by disease-linked mutations. However, which of the several functions of CFH drives this self-surface selectivity remains unknown. To address this, we expressed human CFH mutants in We found that recombinant I62-CFH (protective against age-related macular degeneration) and V62-CFH functioned equivalently, matching or outperforming plasma-derived CFH, whereas R53H-CFH, linked to atypical hemolytic uremic syndrome (aHUS), was defective in C3bBb decay-accelerating activity (DAA) and factor I cofactor activity (CA). The aHUS-linked CCP 19 mutant D1119G-CFH had virtually no CA on (self-like) sheep erythrocytes ( ) but retained DAA. The aHUS-linked CCP 20 mutant S1191L/V1197A-CFH (LA-CFH) had dramatically reduced CA on but was less compromised in DAA. D1119G-CFH and LA-CFH both performed poorly at preventing complement-mediated hemolysis of PspCN, a CFH-binding protein domain, binds CFH tightly and increases accessibility of CCPs 19 and 20. PspCN did not improve the DAA of any CFH variant on Conversely, PspCN boosted the CA, on , of I62-CFH, R53H-CFH, and LA-CFH and also enhanced hemolysis protection by I62-CFH and LA-CFH. We conclude that CCPs 19 and 20 are critical for efficient CA on self-surfaces but less important for DAA. Exposing CCPs 19 and 20 with PspCN and thus enhancing CA on self-surfaces may reverse deficiencies of some CFH variants.
[Mh] Termos MeSH primário: Síndrome Hemolítico-Urêmica Atípica/genética
Ativação do Complemento
Degeneração Macular/genética
Mutação
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Síndrome Hemolítico-Urêmica Atípica/metabolismo
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Sítios de Ligação
C3 Convertase da Via Alternativa do Complemento/química
C3 Convertase da Via Alternativa do Complemento/genética
C3 Convertase da Via Alternativa do Complemento/metabolismo
Complemento C3d/química
Complemento C3d/genética
Complemento C3d/metabolismo
Fator H do Complemento/química
Fator H do Complemento/genética
Fator H do Complemento/metabolismo
Fator I do Complemento/química
Fator I do Complemento/genética
Fator I do Complemento/metabolismo
Eritrócitos/química
Hemólise
Seres Humanos
Proteínas Imobilizadas/química
Proteínas Imobilizadas/genética
Proteínas Imobilizadas/metabolismo
Degeneração Macular/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Carneiro Doméstico
Solubilidade
Streptococcus pneumoniae/metabolismo
Propriedades de Superfície
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Immobilized Proteins); 0 (Peptide Fragments); 0 (Recombinant Fusion Proteins); 0 (complement factor H, human); 80295-45-0 (Complement C3d); 80295-65-4 (Complement Factor H); EC 3.4.21.45 (CFI protein, human); EC 3.4.21.45 (Complement Factor I); EC 3.4.21.47 (Complement C3 Convertase, Alternative Pathway)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.795088


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[PMID]:28282489
[Au] Autor:Tan PL; Garrett ME; Willer JR; Campochiaro PA; Campochiaro B; Zack DJ; Ashley-Koch AE; Katsanis N
[Ad] Endereço:Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, United States 2Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, United States.
[Ti] Título:Systematic Functional Testing of Rare Variants: Contributions of CFI to Age-Related Macular Degeneration.
[So] Source:Invest Ophthalmol Vis Sci;58(3):1570-1576, 2017 Mar 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Genome-wide association (GWAS) and sequencing studies for AMD have highlighted the importance of coding variants at loci that encode components of the complement pathway. However, assessing the contribution of such alleles to AMD, especially when they are rare, remains coarse, in part because of the persistent challenge in establishing their functional relevance. Others and we have shown previously that rare alleles in complement factor I (CFI) can be tested functionally using a surrogate in vivo assay of retinal vascularization in zebrafish embryos. Here, we have implemented and scaled these tools to assess the overall contribution of rare alleles in CFI to AMD. Methods: We performed targeted sequencing of CFI in 731 AMD patients, followed by replication in a second patient cohort of 511 older healthy individuals. Systematic functional testing of all alleles and post-hoc statistical analysis of functional variants was also performed. Results: We discovered 20 rare coding nonsynonymous variants, including the previously reported G119R allele. In vivo testing led to the identification of nine variants that alter CFI; six of which are associated with hypoactive complement factor I (FI). Post-hoc analysis in ethnically matched, population controls showed six of these to be present exclusively in cases. Conclusions: Taken together, our data argue that multiple rare and ultra-rare alleles in CFI contribute to AMD pathogenesis; they improve the precision of the assessment of the contribution of CFI to AMD; and they offer a rational route to establishing both causality and direction of allele effect for genes associated with this disorder.
[Mh] Termos MeSH primário: Fator I do Complemento/genética
DNA/genética
Predisposição Genética para Doença
Estudo de Associação Genômica Ampla/métodos
Degeneração Macular/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Alelos
Animais
Fator I do Complemento/metabolismo
Feminino
Genótipo
Seres Humanos
Degeneração Macular/diagnóstico
Degeneração Macular/metabolismo
Masculino
Meia-Idade
Peixe-Zebra/embriologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA); EC 3.4.21.45 (Complement Factor I)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170311
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-20867


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[PMID]:27643879
[Au] Autor:Velazquez-Villoria A; Recalde S; Anter J; Bezunartea J; Hernandez-Sanchez M; García-García L; Alonso E; Ruiz-Moreno JM; Araiz-Iribarren J; Fernandez-Robredo P; García-Layana A
[Ad] Endereço:Ophthalmology Experimental Laboratory, Universidad de Navarra, Pamplona, Spain.
[Ti] Título:Evaluation of 10 AMD Associated Polymorphisms as a Cause of Choroidal Neovascularization in Highly Myopic Eyes.
[So] Source:PLoS One;11(9):e0162296, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Choroidal neovascularization (CNV) commonly occurs in age related macular degeneration and pathological myopia patients. In this study we conducted a case-control prospective study including 431 participants. The aim of this study was to determine the potential association between 10 single nucleotide polymorphisms (SNPs) located in 4 different genetic regions (CFI, COL8A1, LIPC, and APOE), and choroidal neovascularization in age-related macular degeneration and the development of choroidal neovascularization in highly myopic eyes of a Caucasian population. Univariate and multivariate logistic regression analysis adjusted for age, sex and hypertension was performed for each allele, genotype and haplotype frequency analysis. We found that in the univariate analysis that both single-nucleotide polymorphisms in COL8A1 gene (rs13095226 and rs669676) together with age, sex and hypertension were significantly associated with myopic CNV development in Spanish patients (p<0.05). After correcting for multiple testing none of the polymorphisms studied remained significantly associated with myopic CNV (p>0.05); however, analysis of the axial length between genotypes of rs13095226 revealed an important influence of COL8A1 in the development of CNV in high myopia. Furthermore we conducted a meta-analysis of COL8A1, CFI and LIPC genes SNPs (rs669676, rs10033900 and rs10468017) and found that only rs669676 of these SNPs were associated with high myopia neovascularization.
[Mh] Termos MeSH primário: Neovascularização de Coroide/genética
Degeneração Macular/genética
Miopia Degenerativa/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Idoso
Apolipoproteínas E/genética
Corioide/irrigação sanguínea
Corioide/patologia
Neovascularização de Coroide/complicações
Neovascularização de Coroide/patologia
Colágeno Tipo VIII/genética
Fator I do Complemento/genética
Feminino
Seres Humanos
Lipase/genética
Degeneração Macular/complicações
Degeneração Macular/patologia
Masculino
Meia-Idade
Miopia Degenerativa/complicações
Miopia Degenerativa/patologia
Retina/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ApoE protein, human); 0 (Apolipoproteins E); 0 (Col8A1 protein, human); 0 (Collagen Type VIII); EC 3.1.1.3 (LIPH protein, human); EC 3.1.1.3 (Lipase); EC 3.4.21.45 (CFI protein, human); EC 3.4.21.45 (Complement Factor I)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160920
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0162296


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Vasconcellos, Silvio A
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[PMID]:26976804
[Au] Autor:Castiblanco-Valencia MM; Fraga TR; Breda LC; Vasconcellos SA; Figueira CP; Picardeau M; Wunder E; Ko AI; Barbosa AS; Isaac L
[Ad] Endereço:Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
[Ti] Título:Acquisition of negative complement regulators by the saprophyte Leptospira biflexa expressing LigA or LigB confers enhanced survival in human serum.
[So] Source:Immunol Lett;173:61-8, 2016 05.
[Is] ISSN:1879-0542
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Leptospiral immunoglobulin-like (Lig) proteins are surface exposed molecules present in pathogenic but not in saprophytic Leptospira species. We have previously shown that Lig proteins interact with the soluble complement regulators Factor H (FH), FH like-1 (FHL-1), FH related-1 (FHR-1) and C4b Binding Protein (C4BP). In this study, we used the saprophyte L. biflexa serovar Patoc as a surrogate host to address the specific role of LigA and LigB proteins in leptospiral complement evasion. L. biflexa expressing LigA or LigB was able to acquire FH and C4BP. Bound complement regulators retained their cofactor activities of FI in the proteolytic cleavage of C3b and C4b. Moreover, heterologous expression of ligA and ligB genes in the saprophyte L. biflexa enhanced bacterial survival in human serum. Complement deposition on lig-transformed L. biflexa was assessed by flow cytometry analysis. With regard to MAC deposition, L. biflexa expressing LigA or LigB presented an intermediate profile: MAC deposition levels were greater than those found in the pathogenic L. interrogans, but lower than those observed for L. biflexa wildtype. In conclusion, Lig proteins contribute to in vitro control of complement activation on the leptospiral surface, promoting an increased bacterial survival in human serum.
[Mh] Termos MeSH primário: Antígenos de Bactérias/metabolismo
Fator I do Complemento/metabolismo
Evasão da Resposta Imune
Leptospira/fisiologia
Leptospirose/imunologia
[Mh] Termos MeSH secundário: Antígenos de Bactérias/imunologia
Sobrevivência Celular
Complemento C3b/metabolismo
Complemento C4b/metabolismo
Fator H do Complemento/metabolismo
Complexo de Ataque à Membrana do Sistema Complemento/imunologia
Cadeia Alimentar
Seres Humanos
Leptospira/patogenicidade
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, Bacterial); 0 (Complement Membrane Attack Complex); 0 (LigA-m protein, Leptospira interrogans); 0 (LigB-m protein, Leptospira interrogans); 80295-43-8 (Complement C3b); 80295-50-7 (Complement C4b); 80295-65-4 (Complement Factor H); EC 3.4.21.45 (Complement Factor I)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160316
[St] Status:MEDLINE


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[PMID]:26918864
[Au] Autor:Sakurada Y; Yoneyama S; Sugiyama A; Tanabe N; Kikushima W; Mabuchi F; Kume A; Kubota T; Iijima H
[Ad] Endereço:Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
[Ti] Título:Prevalence and Genetic Characteristics of Geographic Atrophy among Elderly Japanese with Age-Related Macular Degeneration.
[So] Source:PLoS One;11(2):e0149978, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To investigate the prevalence and genetic characteristics of geographic atrophy (GA) among elderly Japanese with advanced age-related macular degeneration (AMD) in a clinic-based study. METHODS: Two-hundred and ninety consecutive patients with advanced AMD were classified into typical neovascular AMD, polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP) or geographic atrophy (GA). Genetic variants of ARMS2 A69S (rs10490924) and CFH I62V (rs800292) were genotyped using TaqMan Genotyping Assays. The clinical and genetic characteristics were compared between patients with and without GA. RESULTS: The number of patients diagnosed as having typical neovascular AMD, PCV, RAP and GA were 98 (33.8%), 151 (52.1%), 22 (7.5%) and 19 (6.6%), respectively. Of 19 patients with GA, 13 patients (68.4%) had unilateral GA with exudative AMD in the contralateral eye. Patients with GA were significantly older, with a higher prevalence of reticular pseudodrusen, bilateral involvement of advanced AMD and T-allele frequency of ARMS2 A69S compared with those with typical AMD and PCV; although there were no differences in the genetic and clinical characteristics among patients with GA and RAP. CONCLUSIONS: The prevalence of GA was 6.6% among elderly Japanese with AMD. Patients with GA and RAP exhibited genetic and clinical similarities.
[Mh] Termos MeSH primário: Cegueira/etiologia
Fator I do Complemento/genética
Atrofia Geográfica/epidemiologia
Atrofia Geográfica/genética
Proteínas/genética
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Envelhecimento
Grupo com Ancestrais do Continente Asiático/genética
Corioide/irrigação sanguínea
Corioide/patologia
Neovascularização de Coroide/patologia
Feminino
Frequência do Gene
Atrofia Geográfica/classificação
Seres Humanos
Japão/epidemiologia
Masculino
Prevalência
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ARMS2 protein, human); 0 (Proteins); EC 3.4.21.45 (CFI protein, human); EC 3.4.21.45 (Complement Factor I)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160310
[Lr] Data última revisão:
160310
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160227
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0149978


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[PMID]:26900322
[Au] Autor:Dai ML; Huang XF; Wang QF; Cai WJ; Jin ZB; Wang Y
[Ad] Endereço:The Eye Hospital of Wenzhou Medical University, State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou 325027, China.
[Ti] Título:CFI-rs7356506 polymorphisms associated with Vogt-Koyanagi-Harada syndrome.
[So] Source:Mol Vis;22:9-17, 2016.
[Is] ISSN:1090-0535
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Complement factor I (CFI) plays an important role in complement activation pathways and is known to affect the development of uveitis. The present study was performed to investigate the existence of an association between CFI genetic polymorphisms and Vogt-Koyanagi-Harada (VKH) syndrome. METHODS: A total of 100 patients diagnosed with VKH syndrome and 300 healthy controls were recruited for the study. Two milliliters of peripheral blood were collected in a sterile anticoagulative tube. CFI-rs7356506 polymorphisms were genotyped using Sequenom MassARRAY technology. Allele and genotype frequencies were compared between patients and controls using a χ(2) test. The analyses were stratified for recurrent status, complicated cataract status, and steroid-sensitive status. RESULTS: No significant association was found between CFI-rs7356506 polymorphisms and VKH syndrome. However, patients with recurrent VKH syndrome had lower frequencies of the G allele and GG homozygosity in CFI-rs7356506 when compared to the controls (p=0.016, odds ratio [OR]=0.429, 95% confidence interval [CI]=0.212-0.871; p=0.014, OR=0.364, 95% CI=0.158-0.837, respectively). Furthermore, there were significant decreases in the frequencies of the G allele and GG homozygosity in CFI-rs7356506 in patients with VKH syndrome with complicated cataract compared to the controls (p<0.001, OR=0.357, 95% CI=0.197-0.648; p<0.001, OR=0.273, 95% CI=0.135-0.551, respectively). Nevertheless, no significant association with patients with VKH syndrome in steroid-sensitive statuses was detected for CFI-rs7356506 polymorphisms. CONCLUSIONS: Our results indicate that CFI polymorphisms are not significantly associated with VKH syndrome; nevertheless, we identified a trend for the association of CFI-7356506 with VKH syndrome that depends on the recurrent status and the complicated cataract status but not on the steroid-sensitive status.
[Mh] Termos MeSH primário: Fator I do Complemento/genética
Polimorfismo de Nucleotídeo Único
Síndrome Uveomeningoencefálica/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Estudos de Casos e Controles
Feminino
Frequência do Gene
Técnicas de Genotipagem
Seres Humanos
Masculino
Meia-Idade
Polimorfismo de Fragmento de Restrição
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 3.4.21.45 (CFI protein, human); EC 3.4.21.45 (Complement Factor I)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160223
[St] Status:MEDLINE


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[PMID]:26826462
[Au] Autor:Szarvas N; Szilágyi Á; Csuka D; Takács B; Rusai K; Müller T; Arbeiter K; Réti M; Haris Á; Wagner L; Török S; Kelen K; Szabó AJ; Reusz GS; Morgan BP; Prohászka Z
[Ad] Endereço:3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
[Ti] Título:Genetic analysis and functional characterization of novel mutations in a series of patients with atypical hemolytic uremic syndrome.
[So] Source:Mol Immunol;71:10-22, 2016 Mar.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Atypical hemolytic uremic syndrome (aHUS) is a rare disorder caused by dysregulation of the complement alternative pathway, and associated with mutations in genes of complement components and regulators. In the recent years several studies have been published describing these mutations, however, no data is available from the Central and Eastern European region. In this study we present a detailed genetic analysis of our 30 patients, hospitalized with the diagnosis of aHUS in the past 7 years. We analyzed the genetic variants of genes CFH, CFI, CD46, THBD, CFB and C3; furthermore the possible effect of mutations that may alter the function or level of factor H protein was also investigated. We identified 27 (12 novel and 15 previously described) potentially disease-causing mutations in the candidate genes in 23 patients. Genetic analysis of family members revealed that in most cases the disease develops in individuals with multiple genetic risk factors, which may explain the low penetrance of the mutations. Here we showed that two novel mutations (p.W198R, p.P1161T) and a previously reported one (p.R1215Q) in CFH caused impaired regulation as indicated by increased lysis in hemolytic test, while four CFH mutations (p.V609D, p.S722X, p.T1216del and p.C448Y) were associated with decreased factor H protein level in serum as determined by allele-specific immunoassay. These results further point to the necessity of complete genetic workup of patients with aHUS and to the importance of functional characterization of novel variations.
[Mh] Termos MeSH primário: Síndrome Hemolítico-Urêmica Atípica/genética
Fator H do Complemento/genética
Predisposição Genética para Doença/genética
Mutação
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Pré-Escolar
Complemento C3/genética
Fator B do Complemento/genética
Fator I do Complemento/genética
Análise Mutacional de DNA
Ensaio de Imunoadsorção Enzimática
Feminino
Genótipo
Seres Humanos
Recém-Nascido
Masculino
Meia-Idade
Reação em Cadeia da Polimerase Multiplex
Polimorfismo de Fragmento de Restrição
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Complement C3); 80295-65-4 (Complement Factor H); EC 3.4.21.45 (Complement Factor I); EC 3.4.21.47 (Complement Factor B)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160316
[Lr] Data última revisão:
160316
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160131
[St] Status:MEDLINE


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[PMID]:26795916
[Au] Autor:Larsen CP; Durfee T; Wilson JD; Beggs ML
[Ad] Endereço:Nephropath, Little Rock, Arkansas. Electronic address: chris.larsen@nephropath.com.
[Ti] Título:A Custom Targeted Next-Generation Sequencing Gene Panel for the Diagnosis of Genetic Nephropathies.
[So] Source:Am J Kidney Dis;67(6):992-3, 2016 06.
[Is] ISSN:1523-6838
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Testes Genéticos/métodos
Glomerulosclerose Segmentar e Focal/genética
Insuficiência Renal Crônica/genética
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Adolescente
Adulto
Alquil e Aril Transferases/genética
Apolipoproteína L1
Apolipoproteínas/genética
Criança
Pré-Escolar
Colágeno Tipo IV/genética
Fator I do Complemento/genética
Feminino
Glomerulosclerose Segmentar e Focal/diagnóstico
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Nefropatias/diagnóstico
Nefropatias/genética
Lipoproteínas HDL/genética
Masculino
Proteínas de Membrana/genética
Proteínas dos Microfilamentos/genética
Insuficiência Renal Crônica/diagnóstico
Análise de Sequência de DNA
Adulto Jovem
[Pt] Tipo de publicação:LETTER; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (APOL1 protein, human); 0 (Adaptor Proteins, Signal Transducing); 0 (Apolipoprotein L1); 0 (Apolipoproteins); 0 (COL4A4 protein, human); 0 (COL4A5 protein, human); 0 (Collagen Type IV); 0 (INF2 protein, human); 0 (Lipoproteins, HDL); 0 (Membrane Proteins); 0 (Microfilament Proteins); 0 (NPHP1 protein, human); EC 2.5.- (Alkyl and Aryl Transferases); EC 2.5.1.- (4-hydroxybenzoate polyprenyltransferase); EC 3.4.21.45 (CFI protein, human); EC 3.4.21.45 (Complement Factor I)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160123
[St] Status:MEDLINE


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[PMID]:26767664
[Au] Autor:Saksens NT; Geerlings MJ; Bakker B; Schick T; Daha MR; Fauser S; Boon CJ; de Jong EK; Hoyng CB; den Hollander AI
[Ad] Endereço:Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
[Ti] Título:Rare Genetic Variants Associated With Development of Age-Related Macular Degeneration.
[So] Source:JAMA Ophthalmol;134(3):287-93, 2016 Mar.
[Is] ISSN:2168-6173
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:IMPORTANCE: Rare variants in the complement genes CFH, CFI, C9, and C3 have been found to be highly associated with age-related macular degeneration (AMD); however, the effect on clinical characteristics and familial segregation by these variants is lacking. OBJECTIVES: To determine the contribution of rare CFH Arg1210Cys, CFI Gly119Arg, C9 Pro167Ser, and C3 Lys155Gln variants in the development of AMD in 22 multiplex families and to describe clinical differences in carriers vs noncarriers in these families and a large case-control cohort. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case-control study included 114 affected and 60 unaffected members of 22 multiplex families with AMD as well as 1589 unrelated patients with AMD and 1386 unrelated control individuals enrolled in the European Genetic Database (EUGENDA). Patients were recruited from March 29, 2006, to April 26, 2013, and data were collected from April 20, 2012, to May 7, 2014. All participants underwent an extensive ophthalmic examination and completed a questionnaire. Venous blood samples were obtained from all participants for genetic analysis, including whole-exome sequencing and measurements of complement activation. Data were analyzed from September 23, 2014, to November 4, 2015. MAIN OUTCOMES AND MEASURES: Differences between carriers and noncarriers of rare variants in age at onset of symptoms, the family history of AMD, complement activation levels (C3d:C3 ratio), the presence of reticular pseudodrusen, and AMD phenotype. RESULTS: Among the 114 affected and 60 unaffected members of 22 multiplex families with AMD and the 1598 unrelated patients with AMD and 1386 controls in the EUGENDA cohort who underwent analysis, the presence of the CFI Gly119Arg, C9 Pro167Ser, or C3 Lys155Gln variant was confirmed in 18 individuals in 5 families but did not completely segregate with the disease. In the case-control cohort, the 91 affected carriers of these variants were younger at symptom onset (mean [SD] age, 67.4 [8.5] vs 71.3 [8.9] years; P = .01) and more often reported a positive family history (35 of 79 [44.3%] vs 367 of 1201 [30.6%]; P = .008) compared with the 1498 noncarriers. Patients with advanced atrophic AMD carried these rare variants more frequently than patients with neovascular AMD (11 of 93 [11.8%] vs 40 of 835 [4.8%]; P = .04). CONCLUSIONS AND RELEVANCE: Previously reported rare variants do not completely segregate within families with AMD. However, patients carrying these rare variants differ clinically from noncarriers by an earlier age at symptom onset, higher prevalence of a positive family history, and AMD phenotype. These results suggest that genetic tests for AMD might be designed to detect common and rare genetic variants, especially in families, because rare variants contribute to the age at onset and progression of the disease.
[Mh] Termos MeSH primário: Complemento C3/genética
Complemento C9/genética
Fator I do Complemento/genética
Atrofia Geográfica/genética
Polimorfismo de Nucleotídeo Único
Degeneração Macular Exsudativa/genética
[Mh] Termos MeSH secundário: Idoso
Estudos de Casos e Controles
Fator H do Complemento/genética
Feminino
Técnicas de Genotipagem
Atrofia Geográfica/diagnóstico
Atrofia Geográfica/fisiopatologia
Heterozigoto
Seres Humanos
Masculino
Meia-Idade
Razão de Chances
Linhagem
Reação em Cadeia da Polimerase
Estudos Retrospectivos
Acuidade Visual/fisiologia
Degeneração Macular Exsudativa/diagnóstico
Degeneração Macular Exsudativa/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Complement C3); 0 (Complement C9); 0 (complement factor H, human); 80295-65-4 (Complement Factor H); EC 3.4.21.45 (Complement Factor I)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160311
[Lr] Data última revisão:
160311
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160116
[St] Status:MEDLINE
[do] DOI:10.1001/jamaophthalmol.2015.5592



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