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[PMID]:28467818
[Au] Autor:Janda CY; Dang LT; You C; Chang J; de Lau W; Zhong ZA; Yan KS; Marecic O; Siepe D; Li X; Moody JD; Williams BO; Clevers H; Piehler J; Baker D; Kuo CJ; Garcia KC
[Ad] Endereço:Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, and Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
[Ti] Título:Surrogate Wnt agonists that phenocopy canonical Wnt and ß-catenin signalling.
[So] Source:Nature;545(7653):234-237, 2017 05 11.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing ß-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic ß-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.
[Mh] Termos MeSH primário: Transdução de Sinais
Proteínas Wnt/agonistas
Proteínas Wnt/metabolismo
Via de Sinalização Wnt
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Linhagem da Célula
Proliferação Celular
Receptores Frizzled/metabolismo
Células HEK293
Hepatócitos/citologia
Hepatomegalia/metabolismo
Hepatomegalia/patologia
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Intestinos/citologia
Ligantes
Fígado/metabolismo
Fígado/patologia
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Células Mesenquimais Estromais/citologia
Células Mesenquimais Estromais/metabolismo
Camundongos
Modelos Moleculares
Organoides/citologia
Organoides/metabolismo
Multimerização Proteica
Solubilidade
Técnicas de Cultura de Tecidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Frizzled Receptors); 0 (Ligands); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Wnt Proteins); 0 (beta Catenin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180217
[Lr] Data última revisão:
180217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1038/nature22306


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[PMID]:29176883
[Au] Autor:Sebastian A; Hum NR; Murugesh DK; Hatsell S; Economides AN; Loots GG
[Ad] Endereço:Lawrence Livermore National Laboratories, Physical and Life Sciences Directorate, Livermore, CA, United States of America.
[Ti] Título:Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts.
[So] Source:PLoS One;12(11):e0188264, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Wnt3a is a major regulator of bone metabolism however, very few of its target genes are known in bone. Wnt3a preferentially signals through transmembrane receptors Frizzled and co-receptors Lrp5/6 to activate the canonical signaling pathway. Previous studies have shown that the canonical Wnt co-receptors Lrp5 and Lrp6 also play an essential role in normal postnatal bone homeostasis, yet, very little is known about specific contributions by these co-receptors in Wnt3a-dependent signaling. We used high-throughput sequencing technology to identify target genes regulated by Wnt3a in osteoblasts and to elucidate the role of Lrp5 and Lrp6 in mediating Wnt3a signaling. Our study identified 782 genes regulated by Wnt3a in primary calvarial osteoblasts. Wnt3a up-regulated the expression of several key regulators of osteoblast proliferation/ early stages of differentiation while inhibiting genes expressed in later stages of osteoblastogenesis. We also found that Lrp6 is the key mediator of Wnt3a signaling in osteoblasts and Lrp5 played a less significant role in mediating Wnt3a signaling.
[Mh] Termos MeSH primário: Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Osteoblastos/metabolismo
Receptores Wnt/metabolismo
Transdução de Sinais
Proteína Wnt3A/metabolismo
[Mh] Termos MeSH secundário: Animais
Osso e Ossos/metabolismo
Diferenciação Celular/genética
Regulação para Baixo/genética
Perfilação da Expressão Gênica
Ontologia Genética
Camundongos Knockout
Osteogênese/genética
Fenótipo
Transcriptoma/genética
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Receptors, Wnt); 0 (Wnt3A Protein)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188264


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[PMID]:29181528
[Au] Autor:Tang M; Sun L; Hu A; Yuan M; Yang Y; Peng X; Ding X
[Ad] Endereço:State Key Laboratory of Ophthalmology, Retina Division, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
[Ti] Título:Mutation Spectrum of the LRP5, NDP, and TSPAN12 Genes in Chinese Patients With Familial Exudative Vitreoretinopathy.
[So] Source:Invest Ophthalmol Vis Sci;58(13):5949-5957, 2017 Nov 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: LRP5, NDP, and TSPAN12 are known to be associated with familial exudative vitreoretinopathy (FEVR). In this study, a comprehensive mutation screening for the three genes was performed in patients with a clinical diagnosis of FEVR in Han Chinese. Methods: Genomic DNA and clinical data were collected from 100 probands and their family members. Sanger sequencing was performed to screen for LRP5, NDP, and TSPAN12 mutations and phenotype-genotype correlation was analyzed. Results: There were 23 causative mutations identified in 23 unrelated probands (10/23 in LRP5, 8/23 in TSPAN12, and 5/23 in NDP). Apart from NDP mutations, only two LRP5 mutations inherited in an autosomal recessive manner. Among the 23 causative mutations, 13 were novel variants (4/10 in LRP5, 6/8 in TSPAN12, and 3/5 in NDP). According to the modified classification system, statistical significance was observed in the distribution of mutated genes (P = 0.049). None of the causative mutations was found in group I FEVR. Probands with LRP5 or NDP mutations were mainly categorized into group III and IV, TSPAN12 mutations were mainly observed in probands with group IV and V FEVR. Conclusions: The detection rate for mutations in the three known genes was 23%. Mutations in LRP5 and TSPAN12 were more frequent, accounting for 10% and 8%, respectively. The NDP mutations were only identified in 6% in this cohort. There were 13 novel variants found, which provided a deeper understanding of this disease. Potential phenotype-genotype correlation was observed in the modified system. TSPAN12 mutations might lead to the most severe phenotype.
[Mh] Termos MeSH primário: DNA/genética
Proteínas do Olho/genética
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Mutação
Proteínas do Tecido Nervoso/genética
Doenças Retinianas/genética
Tetraspaninas/genética
[Mh] Termos MeSH secundário: China/epidemiologia
Análise Mutacional de DNA
Proteínas do Olho/metabolismo
Feminino
Estudos de Associação Genética
Seres Humanos
Incidência
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Masculino
Proteínas do Tecido Nervoso/metabolismo
Linhagem
Fenótipo
Doenças Retinianas/epidemiologia
Doenças Retinianas/metabolismo
Tetraspaninas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eye Proteins); 0 (LRP5 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (NDP protein, human); 0 (Nerve Tissue Proteins); 0 (TSPAN12 protein, human); 0 (Tetraspanins); 9007-49-2 (DNA)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171204
[Lr] Data última revisão:
171204
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-22577


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[PMID]:28974197
[Au] Autor:Correa-Rodríguez M; Viatte S; Massey J; Schmidt-RioValle J; Rueda-Medina B; Orozco G
[Ad] Endereço:Faculty of Health Sciences, University of Granada, Av. Ilustración, 60, 18016, Granada, Spain. macoro@ugr.es.
[Ti] Título:Analysis of SNP-SNP interactions and bone quantitative ultrasound parameter in early adulthood.
[So] Source:BMC Med Genet;18(1):107, 2017 Oct 03.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Osteoporosis individual susceptibility is determined by the interaction of multiple genetic variants and environmental factors. The aim of this study was to conduct SNP-SNP interaction analyses in candidate genes influencing heel quantitative ultrasound (QUS) parameter in early adulthood to identify novel insights into the mechanism of disease. METHODS: The study population included 575 healthy subjects (mean age 20.41; SD 2.36). To assess bone mass QUS was performed to determine Broadband ultrasound attenuation (BUA, dB/MHz). A total of 32 SNPs mapping to loci that have been characterized as genetic markers for QUS and/or BMD parameters were selected as genetic markers in this study. The association of all possible SNP pairs with QUS was assessed by linear regression and a SNP-SNP interaction was defined as a significant departure from additive effects. RESULTS: The pairwise SNP-SNP analysis showed multiple interactions. The interaction comprising SNPs rs9340799 and rs3736228 that map in the ESR1 and LRP5 genes respectively, revealed the lowest p value after adjusting for confounding factors (p-value = 0.001, ß (95% CI) = 14.289 (5.548, 23.029). In addition, our model reported others such as TMEM135-WNT16 (p = 0.007, ß(95%CI) = 9.101 (2.498, 15.704), ESR1-DKK1 (p = 0.012, ß(95%CI) = 13.641 (2.959, 24.322) or OPG-LRP5 (p = 0.012, ß(95%CI) = 8.724 (1.936, 15.512). However, none of the detected interactions remain significant considering the Bonferroni significance threshold for multiple testing (p<0.0001). CONCLUSION: Our analysis of SNP-SNP interaction in candidate genes of QUS in Caucasian young adults reveal several interactions, especially between ESR1 and LRP5 genes, that did not reach statistical significance. Although our results do not support a relevant genetic contribution of SNP-SNP epistatic interactions to QUS in young adults, further studies in larger independent populations would be necessary to support these preliminary findings.
[Mh] Termos MeSH primário: Densidade Óssea/genética
Calcâneo/diagnóstico por imagem
Marcadores Genéticos/genética
Osteoporose/diagnóstico
Polimorfismo de Nucleotídeo Único
Ultrassonografia/métodos
[Mh] Termos MeSH secundário: Adulto
Remodelação Óssea
Receptor alfa de Estrogênio/genética
Feminino
Voluntários Saudáveis
Seres Humanos
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Masculino
Osteoporose/diagnóstico por imagem
Osteoporose/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Estrogen Receptor alpha); 0 (Genetic Markers); 0 (LRP5 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (estrogen receptor alpha, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0468-6


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[PMID]:28694256
[Au] Autor:Ahn Y; Sims C; Murray MJ; Kuhlmann PK; Fuentes-Antrás J; Weatherbee SD; Krumlauf R
[Ad] Endereço:Stowers Institute for Medical Research, Kansas City, MO 64110, USA youngwook_ahn@brown.edu rek@stowers.org.
[Ti] Título:Multiple modes of Lrp4 function in modulation of Wnt/ß-catenin signaling during tooth development.
[So] Source:Development;144(15):2824-2836, 2017 08 01.
[Is] ISSN:1477-9129
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:During development and homeostasis, precise control of Wnt/ß-catenin signaling is in part achieved by secreted and membrane proteins that negatively control activity of the Wnt co-receptors Lrp5 and Lrp6. Lrp4 is related to Lrp5/6 and is implicated in modulation of Wnt/ß-catenin signaling, presumably through its ability to bind to the Wise (Sostdc1)/sclerostin (Sost) family of Wnt antagonists. To gain insights into the molecular mechanisms of Lrp4 function in modulating Wnt signaling, we performed an array of genetic analyses in murine tooth development, where Lrp4 and Wise play important roles. We provide genetic evidence that Lrp4 mediates the Wnt inhibitory function of Wise and also modulates Wnt/ß-catenin signaling independently of Wise. Chimeric receptor analyses raise the possibility that the Lrp4 extracellular domain interacts with Wnt ligands, as well as the Wnt antagonists. Diverse modes of Lrp4 function are supported by severe tooth phenotypes of mice carrying a human mutation known to abolish Lrp4 binding to Sost. Our data suggest a model whereby Lrp4 modulates Wnt/ß-catenin signaling via interaction with Wnt ligands and antagonists in a context-dependent manner.
[Mh] Termos MeSH primário: Receptores de LDL/metabolismo
Dente/embriologia
Dente/metabolismo
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas Morfogenéticas Ósseas/deficiência
Proteínas Morfogenéticas Ósseas/genética
Proteínas Morfogenéticas Ósseas/metabolismo
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Camundongos
Camundongos Mutantes
Receptores de LDL/deficiência
Receptores de LDL/genética
Dente/patologia
Via de Sinalização Wnt/genética
Via de Sinalização Wnt/fisiologia
beta Catenina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bone Morphogenetic Proteins); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Lrp4 protein, mouse); 0 (Lrp5 protein, mouse); 0 (Lrp6 protein, mouse); 0 (Receptors, LDL); 0 (Sostdc1 protein, mouse); 0 (beta Catenin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1242/dev.150680


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[PMID]:28682874
[Au] Autor:Zhang ZC; Liu JX; Shao ZW; Pu FF; Wang BC; Wu Q; Zhang YK; Zeng XL; Guo XD; Yang SH; He TC
[Ad] Endereço:aDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China bMolecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, IL.
[Ti] Título:In vitro effect of microRNA-107 targeting Dkk-1 by regulation of Wnt/ß-catenin signaling pathway in osteosarcoma.
[So] Source:Medicine (Baltimore);96(27):e7245, 2017 Jul.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The aim of the study was to explore the effects of microRNA-107 (miR-107) by targeting Dkk-1 on osteosarcoma (OS) via the Wnt/ß-catenin signaling pathway. METHODS: OS and adjacent tissues were collected from 67 patients diagnosed with OS. Expressions of miR-107, Dkk-1, LRP5, ß-catenin, and c-Myc were detected by the quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The dual-luciferase reporter gene assay was performed to observe the relationship between miR-107 and Dkk-1.Transfected cells were divided into different investigating groups designated as Inhibitor, Mimic, siRNA, Inhibitor + siRNA, negative control (NC), and blank groups. qRT-PCR and Western blotting were used to detect expressions of miR-107, Dkk-1, ß-catenin, Bcl-2, c-Myc, Caspase-3, and PARP. Cell counting kit-8 (CCK-8), flow cytometry (FCM), colony-formation efficiency (CFE), and subcutaneous tumorigenicity assays were all utilized for to determine cell proliferation, apoptosis, colony-forming, and tumorigenic abilities. RESULTS: Dkk-1 is the target gene of miR-107. Decreased expressions of miR-107, LRP5, ß-catenin, and c-Myc, and increased expressions of Dkk-1 were found in OS tissues. The Mimic and siRNA groups exhibited decreased proliferation rates, colony-forming abilities, and tumorigenicity and increased apoptosis rates, whereas the inhibitor group showed opposite trends when compared to the blank group. On the other hand, expressions of miR-107, LRP5, ß-catenin, c-Myc, Caspase-3, and PARP were all elevated in the mimic group, whereas expressions of Dkk-1 and Bcl-2 were reduced; opposite trends were observed in the inhibitor group. CONCLUSION: We conclude that miR-107 is likely to inhibit the occurrence and development of OS by down-regulating Dkk-1 via the Wnt/ß-catenin signaling pathway, providing us with a new therapeutic target for the treatment of OS.
[Mh] Termos MeSH primário: Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
MicroRNAs/metabolismo
Osteossarcoma/metabolismo
Via de Sinalização Wnt/fisiologia
[Mh] Termos MeSH secundário: Animais
Apoptose/fisiologia
Caspase 3/metabolismo
Proliferação Celular/fisiologia
Células Cultivadas
Seres Humanos
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Camundongos Nus
MicroRNAs/antagonistas & inibidores
MicroRNAs/genética
Transplante de Neoplasias
Poli(ADP-Ribose) Polimerases/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Proteínas Proto-Oncogênicas c-myc/metabolismo
RNA Interferente Pequeno
Distribuição Aleatória
Proteínas Wnt/metabolismo
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL2 protein, human); 0 (DKK1 protein, human); 0 (Intercellular Signaling Peptides and Proteins); 0 (LRP5 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (MIRN107 microRNA, human); 0 (MYC protein, human); 0 (MicroRNAs); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Proto-Oncogene Proteins c-myc); 0 (RNA, Small Interfering); 0 (Wnt Proteins); 0 (beta Catenin); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 3.4.22.- (CASP3 protein, human); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000007245


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[PMID]:28494495
[Au] Autor:Rao FQ; Cai XB; Cheng FF; Cheng W; Fang XL; Li N; Huang XF; Li LH; Jin ZB
[Ad] Endereço:Division of Ophthalmic Genetics, Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, The Eye Hospital, Wenzhou Medical University, State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou, China.
[Ti] Título:Mutations in LRP5,FZD4, TSPAN12, NDP, ZNF408, or KIF11 Genes Account for 38.7% of Chinese Patients With Familial Exudative Vitreoretinopathy.
[So] Source:Invest Ophthalmol Vis Sci;58(5):2623-2629, 2017 May 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Familial exudative vitreoretinopathy (FEVR) is a severe hereditary retinal disorder characterized by defects in retinal vascular development. To date, six genes have been reported to be responsible for this disease, including LRP5, FZD4, TSPAN12, NDP, ZNF408, and KIF11. The purpose of our study was to investigate the genetic defects in Chinese patients with FEVR through mutational analyses of 31 pedigrees. Methods: Clinical data and peripheral blood were collected from 31 pedigrees with FEVR. All coding sequences and intron/exon junctions were amplified and sequenced comprehensively, followed by cosegregation testing to verify suspected variants in the family members. Finally, we assessed clinical relevance of the identified mutations, according to the standards and guidelines from the American College of Medical Genetics and Genomics. Results: Twelve index cases (12/31, 38.7%) were confirmed to harbor mutations in the known genes, including one previously reported mutation and 11 novel mutations. Among the detected mutations, LRP5 accounted for the largest proportion with a mean mutation rate of 16.1% (5/31, 16.1%), followed by NDP (3/31, 9.7%), FZD4 (2/31, 6.5%), TSPAN12 (1/31, 3.2%), and KIF11 (1/31, 3.2%). All the novel changes were predicted to be pathogenic by a series of bioinformatics analyses. Conclusions: We comprehensively screened six known disease-causing genes in 31 pedigrees with FEVR and achieved a clear picture of the mutation spectrum in Chinese patients with FEVR, which highlights the importance and utility of clinical genetic diagnosis.
[Mh] Termos MeSH primário: Proteínas de Ligação a DNA/genética
Proteínas do Olho/genética
Receptores Frizzled/genética
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Mutação
Proteínas do Tecido Nervoso/genética
Doenças Retinianas/genética
Tetraspaninas/genética
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: China/epidemiologia
Análise Mutacional de DNA
Proteínas de Ligação a DNA/metabolismo
Éxons
Proteínas do Olho/metabolismo
Feminino
Receptores Frizzled/metabolismo
Seres Humanos
Incidência
Cinesina/genética
Cinesina/metabolismo
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Masculino
Proteínas do Tecido Nervoso/metabolismo
Linhagem
Fenótipo
Doenças Retinianas/epidemiologia
Doenças Retinianas/metabolismo
Tetraspaninas/metabolismo
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Eye Proteins); 0 (FZD4 protein, human); 0 (Frizzled Receptors); 0 (KIF11 protein, human); 0 (LRP5 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (NDP protein, human); 0 (Nerve Tissue Proteins); 0 (TSPAN12 protein, human); 0 (Tetraspanins); 0 (Transcription Factors); 0 (ZNF408 protein, human); EC 3.6.4.4 (Kinesin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-21324


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[PMID]:28425175
[Au] Autor:Seo T; Sakon T; Nakazawa S; Nishioka A; Watanabe K; Matsumoto K; Akasaka M; Shioi N; Sawada H; Araki S
[Ad] Endereço:Sugashima Marine Biological Laboratory, Graduate School of Science, Nagoya University, Japan.
[Ti] Título:Haemorrhagic snake venom metalloproteases and human ADAMs cleave LRP5/6, which disrupts cell-cell adhesions in vitro and induces haemorrhage in vivo.
[So] Source:FEBS J;284(11):1657-1671, 2017 Jun.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Snake venom metalloproteases (SVMPs) are members of the a disintegrin and metalloprotease (ADAM) family of proteins, as they possess similar domains. SVMPs are known to elicit snake venom-induced haemorrhage; however, the target proteins and cleavage sites are not known. In this work, we identified a target protein of vascular apoptosis-inducing protein 1 (VAP1), an SVMP, relevant to its ability to induce haemorrhage. VAP1 disrupted cell-cell adhesions by relocating VE-cadherin and γ-catenin from the cell-cell junction to the cytosol, without inducing proteolysis of VE-cadherin. The Wnt receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are known to promote catenin relocation, and are rendered constitutively active in Wnt signalling by truncation. Thus, we examined whether VAP1 cleaves LRP5/6 to induce catenin relocation. Indeed, we found that VAP1 cleaved the extracellular region of LRP6 and LRP5. This cleavage removes four inhibitory ß-propeller structures, resulting in activation of LRP5/6. Recombinant human ADAM8 and ADAM12 also cleaved LRP6 at the same site. An antibody against a peptide including the LRP6-cleavage site inhibited VAP1-induced VE-cadherin relocation and disruption of cell-cell adhesions in cultured cells, and blocked haemorrhage in mice in vivo. Intriguingly, animals resistant to the effects of haemorrhagic snake venom express variants of LRP5/6 that lack the VAP1-cleavage site, or low-density lipoprotein receptor domain class A domains involved in formation of the constitutively active form. The results validate LRP5/6 as physiological targets of ADAMs. Furthermore, they indicate that SVMP-induced cleavage of LRP5/6 causes disruption of cell-cell adhesion and haemorrhage, potentially opening new avenues for the treatment of snake bites.
[Mh] Termos MeSH primário: Proteínas ADAM/metabolismo
Proteínas Reguladoras de Apoptose/metabolismo
Venenos de Crotalídeos/metabolismo
Hemorragia/induzido quimicamente
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia
Metaloendopeptidases/metabolismo
[Mh] Termos MeSH secundário: Proteínas ADAM/farmacologia
Proteína ADAM12/metabolismo
Proteína ADAM12/farmacologia
Sequência de Aminoácidos
Animais
Anticorpos Neutralizantes/farmacologia
Adesão Celular/efeitos dos fármacos
Adesão Celular/fisiologia
Resistência a Medicamentos
Fibrinogênio/metabolismo
Fibronectinas/metabolismo
Células HeLa
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
Masculino
Proteínas de Membrana/metabolismo
Proteínas de Membrana/farmacologia
Camundongos
Modelos Moleculares
Simulação de Acoplamento Molecular
Domínios Proteicos
Estrutura Secundária de Proteína/efeitos dos fármacos
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Especificidade da Espécie
Vertebrados/metabolismo
Via de Sinalização Wnt/efeitos dos fármacos
Via de Sinalização Wnt/fisiologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Neutralizing); 0 (Apoptosis Regulatory Proteins); 0 (Crotalid Venoms); 0 (Fibronectins); 0 (LRP5 protein, human); 0 (LRP6 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Lrp5 protein, mouse); 0 (Lrp6 protein, mouse); 0 (Membrane Proteins); 0 (Recombinant Proteins); 0 (fibrinogen Aalpha); 9001-32-5 (Fibrinogen); EC 3.4.24.- (ADAM Proteins); EC 3.4.24.- (ADAM12 Protein); EC 3.4.24.- (ADAM12 protein, human); EC 3.4.24.- (ADAM8 protein, human); EC 3.4.24.- (Metalloendopeptidases); EC 3.4.24.- (VAP2 protein, Crotalus atrox); EC 3.4.24.- (vascular apoptosis-inducing protein 1, Crotalus atrox)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14066


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[PMID]:28420620
[Au] Autor:Liu YQ; Zhu X; Li SJ; Yang YM; Yang M; Zhao PQ; Zhu XJ
[Ad] Endereço:1. Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu 610072, China; 2. Institute of Laboratory Animal Sciences, Sichuan Academy of Medical Sciences and Sichuan Pro
[Ti] Título:Identification of LRP5 mutations in families with familial exudative vitreoretinopathy.
[So] Source:Yi Chuan;39(3):241-249, 2017 03 20.
[Is] ISSN:0253-9772
[Cp] País de publicação:China
[La] Idioma:eng
[Ab] Resumo:Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disease characterized by defects in the development of periphery retinal vessels. However, the clinical phenotypes of FEVR vary widely from asymptomatic to complete blindness. We analyzed patients from three Chinese families and one sporadic patient with FEVR to investigate the clinical features and disease-causing mutations. Ocular phenotypes included increased ramification of the peripheral retinal vessels, a peripheral avascular zone, inferotemporal dragging of the optic disc and macula, and retinal folds. Peripheral blood DNA samples were obtained from patients with FEVR and their family members. Primers were designed to amplify the coding exons and adjacent intronic regions of the FEVR-causing genes FZD4, LRP5, NDP and TSPAN12. By polymerase chain reactions, each amplicon was subjected to direct Sanger sequencing analysis. Potential pathogenic changes of the sequence variants were analyzed by the orthologous protein sequence alignment and computational prediction software. We identified five LRP5 mutations: three novel heterozygous mutations-p.M181R, p.R399S and p.G503R and two known mutations that were never reported in FEVR patients: p.R494Q and p.G876S. All five mutations involved highly conserved residues and were predicted to be damaging by SIFT and PolyPhen-2. None was present in 500 normal individuals. To assess the pathogenesis of these mutations, wild-type and all five mutant LRP5 proteins were assayed for the ability to activate the Norrin/ß-catenin pathway by established luciferase reporter assays, and all mutants failed to activate the pathway. This study extends the genetic database of the FEVR disease in China and provides a basis for molecular diagnosis of the disease.
[Mh] Termos MeSH primário: Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Doenças Retinianas/genética
[Mh] Termos MeSH secundário: Grupo com Ancestrais do Continente Asiático
Pré-Escolar
China
Éxons/genética
Feminino
Variação Genética
Genótipo
Células HEK293
Seres Humanos
Masculino
Mutação
Linhagem
beta Catenina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (LRP5 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (beta Catenin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170420
[St] Status:MEDLINE
[do] DOI:10.16288/j.yczz.16-339


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[PMID]:28359679
[Au] Autor:Zhang Y; Seid K; Obermayr F; Just L; Neckel PH
[Ad] Endereço:Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany.
[Ti] Título:Activation of Wnt Signaling Increases Numbers of Enteric Neurons Derived From Neonatal Mouse and Human Progenitor Cells.
[So] Source:Gastroenterology;153(1):154-165.e9, 2017 Jul.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Neural stem and progenitor cells from the enteric nervous system (ENS) might serve as a source of cells for treatment of neurogastrointestinal disorders. Before we can use these cells, we must increase our understanding of the signaling mechanisms that regulate proliferation and differentiation. We systematically evaluated the effects of canonical Wnt signaling on proliferation and differentiation of cultured ENS progenitor cells from neonatal mice and humans. METHODS: We isolated ENS progenitors from tunica muscularis of the small intestine of newborn (postnatal day 0) wild-type C57BL/6 mice as well as from Wnt1-Cre2 reporter mice. We also obtained intestinal tissue samples from infants (2 and 7 months old) undergoing surgery for imperforate anus or focal intestinal perforation and isolated ENS cells. ENS cells were cultured under proliferation conditions leading to formation of 3-dimensional spheres, which we activated with Wnt3a and SB216763 in order to activate the ß-catenin-dependent canonical Wnt pathway. We used immunoblot and quantitative polymerase chain reaction to evaluate the molecular response to Wnt stimuli and immunohistochemistry, proliferation, and cell death assays to identify new neurons. RESULTS: In proliferating enterospheres derived from ENS progenitor cells, we verified the expression of Wnt receptors frizzled 1-10 and the co-receptors low-density lipoprotein receptor-related proteins 5 and 6. Pharmacologic stimulation with Wnt agonists led to intracellular accumulation of Wnt-dependent ß-catenin and up-regulated expression of known Wnt target genes axin2, lef1, and lgr5. Activation of the canonical Wnt pathway promoted growth of ENS cell spheres during cell expansion and increased the number of newborn neurons derived from mouse and human progenitor cells. CONCLUSIONS: In studies of human and mouse ENS progenitors, we found activation of the Wnt signaling pathway to promote neurogenesis of the ENS in vitro. The neurogenic effect of Wnt agonists on ENS progenitors supports their use in generation of cell pools for autologous cell replacement therapies.
[Mh] Termos MeSH primário: Diferenciação Celular
Proliferação Celular
Sistema Nervoso Entérico/citologia
Neurônios
RNA Mensageiro/análise
Via de Sinalização Wnt
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Proteína Axina/genética
Contagem de Células
Morte Celular
Proliferação Celular/efeitos dos fármacos
Feminino
Receptores Frizzled/genética
Receptores Frizzled/metabolismo
Expressão Gênica/efeitos dos fármacos
Seres Humanos
Indóis/farmacologia
Lactente
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Fator 1 de Ligação ao Facilitador Linfoide/genética
Masculino
Maleimidas/farmacologia
Camundongos
Camundongos Endogâmicos C57BL
Receptores Acoplados a Proteínas-G/genética
Esferoides Celulares/metabolismo
Células-Tronco
Regulação para Cima
Via de Sinalização Wnt/efeitos dos fármacos
Proteína Wnt3A/farmacologia
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AXIN2 protein, human); 0 (Axin Protein); 0 (Axin2 protein, mouse); 0 (Frizzled Receptors); 0 (Indoles); 0 (LGR5 protein, human); 0 (Lgr5 protein, mouse); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Lymphoid Enhancer-Binding Factor 1); 0 (Maleimides); 0 (RNA, Messenger); 0 (Receptors, G-Protein-Coupled); 0 (SB 216763); 0 (Wnt3A Protein); 0 (beta Catenin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170401
[St] Status:MEDLINE



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