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[PMID]:28469022
[Au] Autor:Chakravorty S; Tanner BCW; Foelber VL; Vu H; Rosenthal M; Ruiz T; Vigoreaux JO
[Ad] Endereço:Department of Biology, University of Vermont, Burlington, VT 05405, USA.
[Ti] Título:Flightin maintains myofilament lattice organization required for optimal flight power and courtship song quality in .
[So] Source:Proc Biol Sci;284(1854), 2017 May 17.
[Is] ISSN:1471-2954
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The indirect flight muscles (IFMs) of and other insects with asynchronous flight muscles are characterized by a crystalline myofilament lattice structure. The high-order lattice regularity is considered an adaptation for enhanced power output, but supporting evidence for this claim is lacking. We show that IFMs from transgenic flies expressing flightin with a deletion of its poorly conserved N-terminal domain ( ) have reduced inter-thick filament spacing and a less regular lattice. This resulted in a decrease in flight ability by 33% and in skinned fibre oscillatory power output by 57%, but had no effect on wingbeat frequency or frequency of maximum power output, suggesting that the underlying actomyosin kinetics is not affected and that the flight impairment arises from deficits in force transmission. Moreover, we show that males produced an abnormal courtship song characterized by a higher sine song frequency and a pulse song with longer pulses and longer inter-pulse intervals (IPIs), the latter implicated in male reproductive success. When presented with a choice, wild-type females chose control males over mutant males in 92% of the competition events. These results demonstrate that flightin N-terminal domain is required for optimal myofilament lattice regularity and IFM activity, enabling powered flight and courtship song production. As the courtship song is subject to female choice, we propose that the low amino acid sequence conservation of the N-terminal domain reflects its role in fine-tuning species-specific courtship songs.
[Mh] Termos MeSH primário: Corte
Proteínas de Drosophila/fisiologia
Drosophila melanogaster/fisiologia
Filaminas/fisiologia
Voo Animal
Proteínas Musculares/fisiologia
Miofibrilas/fisiologia
[Mh] Termos MeSH secundário: Animais
Feminino
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Filamins); 0 (Muscle Proteins); 0 (fln protein, Drosophila)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


  2 / 1084 MEDLINE  
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[PMID]:29240780
[Au] Autor:Lian G; Kanaujia S; Wong T; Sheen V
[Ad] Endereço:Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States of America.
[Ti] Título:FilaminA and Formin2 regulate skeletal, muscular, and intestinal formation through mesenchymal progenitor proliferation.
[So] Source:PLoS One;12(12):e0189285, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The effects of actin dependent molecular mechanisms in coordinating cellular proliferation, migration and differentiation during embryogenesis are not well-understood. We have previously shown that actin-binding Filamin A (FlnA) and actin-nucleating Formin 2 (Fmn2) influence the development of the brain causing microcephaly in mice. In this study, we broaden this phenotype to explore the effects of these two proteins in the development of extra-CNS organ systems, including the gut, muscle, and skeleton. We observed defects in rib and sternum midline closure leading to thoracoabdominal schisis in FlnA+Fmn2 knockout mice, reminiscent of the pentalogy of Cantrell syndrome. These mice exhibit shortened guts, as well as thinned thoracic muscle mass. Immunostaining showed these changes are partially caused by a decrease in the number of presumptive mesenchymal proliferating cells with loss of either FlnA or FlnA+Fmn2. This proliferation defect appears to be in part due to delayed differentiation in these regions. While both FlnA and FlnA+Fmn2 mice show reduced cell death relative to WT control, increased caspase staining was seen in the double null relative to FlnA null suggesting that this could also contribute to the FlnA+Fmn2 phenotype. Therefore FlnA and Fmn2 are likely essential to cell proliferation, differentiation and cell death in a variety of tissues and organs, further reiterating the importance of vesicle trafficking in regulation of development.
[Mh] Termos MeSH primário: Osso e Ossos/citologia
Proliferação Celular/fisiologia
Filaminas/fisiologia
Intestinos/citologia
Células Mesenquimais Estromais/citologia
Proteínas dos Microfilamentos/fisiologia
Músculo Esquelético/citologia
Proteínas Nucleares/fisiologia
[Mh] Termos MeSH secundário: Animais
Camundongos
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Filamins); 0 (Microfilament Proteins); 0 (Nuclear Proteins); 0 (formin 2, mouse)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171215
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189285


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[PMID]:28872460
[Au] Autor:Papizan JB; Garry GA; Brezprozvannaya S; McAnally JR; Bassel-Duby R; Liu N; Olson EN
[Ti] Título:Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice.
[So] Source:J Clin Invest;127(10):3730-3740, 2017 Oct 02.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Maintenance of muscle structure and function depends on the precise organization of contractile proteins into sarcomeres and coupling of the contractile apparatus to the sarcoplasmic reticulum (SR), which serves as the reservoir for calcium required for contraction. Several members of the Kelch superfamily of proteins, which modulate protein stability as substrate-specific adaptors for ubiquitination, have been implicated in sarcomere formation. The Kelch protein Klhl31 is expressed in a muscle-specific manner under control of the transcription factor MEF2. To explore its functions in vivo, we created a mouse model of Klhl31 loss of function using the CRISPR-Cas9 system. Mice lacking Klhl31 exhibited stunted postnatal skeletal muscle growth, centronuclear myopathy, central cores, Z-disc streaming, and SR dilation. We used proteomics to identify several candidate Klhl31 substrates, including Filamin-C (FlnC). In the Klhl31-knockout mice, FlnC protein levels were highly upregulated with no change in transcription, and we further demonstrated that Klhl31 targets FlnC for ubiquitination and degradation. These findings highlight a role for Klhl31 in the maintenance of skeletal muscle structure and provide insight into the mechanisms underlying congenital myopathies.
[Mh] Termos MeSH primário: Músculo Esquelético/metabolismo
Miotonia Congênita/genética
Miotonia Congênita/metabolismo
Fatores de Transcrição/deficiência
[Mh] Termos MeSH secundário: Animais
Filaminas/genética
Filaminas/metabolismo
Fatores de Transcrição MEF2/metabolismo
Camundongos
Camundongos Knockout
Músculo Esquelético/patologia
Miotonia Congênita/patologia
Fatores de Transcrição/metabolismo
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Filamins); 0 (MEF2 Transcription Factors); 0 (Transcription Factors)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE


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[PMID]:28778796
[Au] Autor:Wieczorek K; Wiktorska M; Sacewicz-Hofman I; Boncela J; Lewinski A; Kowalska MA; Niewiarowska J
[Ad] Endereço:Department of Molecular Cell Mechanisms, Medical University of Lodz, Lodz, Poland; Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Lodz, Poland.
[Ti] Título:Filamin A upregulation correlates with Snail-induced epithelial to mesenchymal transition (EMT) and cell adhesion but its inhibition increases the migration of colon adenocarcinoma HT29 cells.
[So] Source:Exp Cell Res;359(1):163-170, 2017 Oct 01.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Filamin A (FLNA) is actin filament cross-linking protein involved in cancer progression. Its importance in regulating cell motility is directly related to the epithelial to mesenchymal transition (EMT) of tumor cells. However, little is known about the mechanism of action of FLNA at this early stage of cancer invasion. Using immunochemical methods, we evaluated the levels and localization of FLNA, pFLNA[Ser2152], ß1 integrin, pß1 integrin[Thr788/9], FAK, pFAK[Y379], and talin in stably transfected HT29 adenocarcinoma cells overexpressing Snail and looked for the effect of Snail in adhesion and migration assays on fibronectin-coated surfaces before and after FLNA silencing. Our findings indicate that FLNA upregulation correlates with Snail-induced EMT in colorectal carcinoma. FLNA localizes in the cytoplasm and at the sites of focal adhesion (FA) of invasive cells. Silencing of FLNA inhibits Snail-induced cell adhesion, reduces the size of FA sites, induces the relocalization of talin from the cytoplasm to the membrane area and augments cell migratory properties. Our findings suggest that FLNA may not act as a classic integrin inhibitor in invasive carcinoma cells, but is involved in other pro-invasive pathways. FLNA upregulation, which correlates with cell metastatic properties, maybe an additional target for combination therapy in colorectal carcinoma tumor progression.
[Mh] Termos MeSH primário: Adenocarcinoma/patologia
Movimento Celular
Neoplasias do Colo/patologia
Transição Epitelial-Mesenquimal
Filaminas/metabolismo
Fatores de Transcrição da Família Snail/metabolismo
Regulação para Cima
[Mh] Termos MeSH secundário: Adenocarcinoma/metabolismo
Adesão Celular
Células Clonais
Neoplasias do Colo/metabolismo
Proteína-Tirosina Quinases de Adesão Focal/metabolismo
Adesões Focais
Inativação Gênica
Células HT29
Seres Humanos
Integrina beta1/metabolismo
Invasividade Neoplásica
Fosforilação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Filamins); 0 (Integrin beta1); 0 (Snail Family Transcription Factors); EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
[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:170806
[St] Status:MEDLINE


  5 / 1084 MEDLINE  
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[PMID]:28732005
[Au] Autor:González-Morales N; Holenka TK; Schöck F
[Ad] Endereço:Department of Biology, McGill University, Montreal, Quebec, Canada.
[Ti] Título:Filamin actin-binding and titin-binding fulfill distinct functions in Z-disc cohesion.
[So] Source:PLoS Genet;13(7):e1006880, 2017 Jul.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many proteins contribute to the contractile properties of muscles, most notably myosin thick filaments, which are anchored at the M-line, and actin thin filaments, which are anchored at the Z-discs that border each sarcomere. In humans, mutations in the actin-binding protein Filamin-C result in myopathies, but the underlying molecular function is not well understood. Here we show using Drosophila indirect flight muscle that the filamin ortholog Cheerio in conjunction with the giant elastic protein titin plays a crucial role in keeping thin filaments stably anchored at the Z-disc. We identify the filamin domains required for interaction with the titin ortholog Sallimus, and we demonstrate a genetic interaction of filamin with titin and actin. Filamin mutants disrupting the actin- or the titin-binding domain display distinct phenotypes, with Z-discs breaking up in parallel or perpendicularly to the myofibril, respectively. Thus, Z-discs require filamin to withstand the strong contractile forces acting on them.
[Mh] Termos MeSH primário: Conectina/genética
Proteínas de Drosophila/genética
Filaminas/genética
Miofibrilas/genética
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/genética
Citoesqueleto de Actina/metabolismo
Actinas/genética
Actinas/metabolismo
Animais
Conectina/metabolismo
Drosophila/genética
Drosophila/metabolismo
Proteínas de Drosophila/metabolismo
Filaminas/metabolismo
Voo Animal
Seres Humanos
Contração Muscular/genética
Músculo Esquelético/metabolismo
Miofibrilas/metabolismo
Fenótipo
Ligação Proteica
Interferência de RNA
Sarcômeros/genética
Sarcômeros/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Connectin); 0 (Drosophila Proteins); 0 (Filamins); 0 (cher protein, Drosophila); 0 (sls protein, Drosophila)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006880


  6 / 1084 MEDLINE  
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[PMID]:28666872
[Au] Autor:Cho Y; Park D; Kim C
[Ad] Endereço:Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea. Electronic address: ycho77@korea.ac.kr.
[Ti] Título:Disruption of TACE-filamin interaction can inhibit TACE-mediated ectodomain shedding.
[So] Source:Biochem Biophys Res Commun;490(3):997-1003, 2017 Aug 26.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ectodomain shedding regulates functions of many membrane proteins through the cleavage of their juxtamembrane region mainly by a disintegrin and metalloproteinase family proteinases. Tumor necrosis factor-alpha converting enzyme (TACE) is known to be responsible for phorbol myristate acetate (PMA)-induced shedding of various membrane proteins. How PMA regulates TACE-dependent shedding and how TACE exhibits substrate specificity without proteolysis of other membrane proteins are questionable. Here, we show that TACE can interact with an actin-binding protein, filamin, through 20th filamin repeat. We found that the interaction between TACE and filamin was increased by PMA treatment. In addition, loss of filamin or specific disruption of TACE-filamin interaction inhibited ectodomain shedding of representative TACE substrates, CD44 and amyloid protein precursor. From these data, we suggest that filamin may work as a scaffold that can recruit TACE and its substrates in a PMA-dependent manner to achieve substrate specificity for TACE.
[Mh] Termos MeSH primário: Proteína ADAM17/metabolismo
Carcinógenos/metabolismo
Filaminas/metabolismo
Serina Endopeptidases/metabolismo
Acetato de Tetradecanoilforbol/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAM17/análise
Linhagem Celular Tumoral
Filaminas/análise
Seres Humanos
Modelos Moleculares
Domínios Proteicos/efeitos dos fármacos
Mapas de Interação de Proteínas/efeitos dos fármacos
Serina Endopeptidases/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carcinogens); 0 (Filamins); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.109 (ST14 protein, human); EC 3.4.24.86 (ADAM17 Protein); EC 3.4.24.86 (ADAM17 protein, human); NI40JAQ945 (Tetradecanoylphorbol Acetate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170702
[St] Status:MEDLINE


  7 / 1084 MEDLINE  
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[PMID]:28650341
[Au] Autor:Pianta A; Arvikar SL; Strle K; Drouin EE; Wang Q; Costello CE; Steere AC
[Ad] Endereço:Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, Massachusetts, USA.
[Ti] Título:Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints.
[So] Source:J Clin Invest;127(8):2946-2956, 2017 Aug 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In rheumatoid arthritis (RA), immunological triggers at mucosal sites, such as the gut microbiota, may promote autoimmunity that affects joints. Here, we used discovery-based proteomics to detect HLA-DR-presented peptides in synovia or peripheral blood mononuclear cells and identified 2 autoantigens, N-acetylglucosamine-6-sulfatase (GNS) and filamin A (FLNA), as targets of T and B cell responses in 52% and 56% of RA patients, respectively. Both GNS and FLNA were highly expressed in synovia. GNS appeared to be citrullinated, and GNS antibody values correlated with anti-citrullinated protein antibody (ACPA) levels. FLNA did not show the same results. The HLA-DR-presented GNS peptide has marked sequence homology with epitopes from sulfatase proteins of the Prevotella sp. and Parabacteroides sp., whereas the HLA-DR-presented FLNA peptide has homology with epitopes from proteins of the Prevotella sp. and Butyricimonas sp., another gut commensal. Patients with T cell reactivity with each self-peptide also had responses to the corresponding microbial peptides, and the levels were directly correlated. Furthermore, HLA-DR molecules encoded by shared-epitope (SE) alleles were predicted to bind these self- and microbial peptides strongly, and these responses were more common in RA patients with SE alleles. Thus, sequence homology between T cell epitopes of 2 self-proteins and a related order of gut microbes may provide a link between mucosal and joint immunity in patients with RA.
[Mh] Termos MeSH primário: Artrite Reumatoide/imunologia
Autoantígenos/imunologia
Autoimunidade/imunologia
Microbioma Gastrointestinal
Articulações/imunologia
Leucócitos Mononucleares/imunologia
[Mh] Termos MeSH secundário: Antirreumáticos/uso terapêutico
Artrite Reumatoide/tratamento farmacológico
Ensaio de Imunoadsorção Enzimática
Epitopos/imunologia
Filaminas/imunologia
Antígenos HLA-DR/imunologia
Seres Humanos
Imunoglobulina A/imunologia
Imunoglobulina G/imunologia
Articulações/patologia
Leucócitos Mononucleares/citologia
Leucócitos Mononucleares/metabolismo
Sulfatases/imunologia
Membrana Sinovial/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antirheumatic Agents); 0 (Autoantigens); 0 (Epitopes); 0 (Filamins); 0 (HLA-DR Antigens); 0 (Immunoglobulin A); 0 (Immunoglobulin G); EC 3.1.6.- (Sulfatases); EC 3.1.6.14 (N-acetylglucosamine-6-sulfatase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE


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[PMID]:28487281
[Au] Autor:Wang H; Guo J; Lin Z; Namgoong S; Oh JS; Kim NH
[Ad] Endereço:Department of Animal Sciences, Chungbuk National University, Cheongju, South Korea.
[Ti] Título:Filamin A is required for spindle migration and asymmetric division in mouse oocytes.
[So] Source:FASEB J;31(8):3677-3688, 2017 Aug.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dynamic changes in the actin network are crucial for the cortical migration of spindles and establishment of polarity, to ensure asymmetric division during meiotic maturation. In this study, filamin A (FLNA) was found to be an essential actin regulator that controlled spindle migration and asymmetric division during oocyte meiosis. FLNA was localized in the cytoplasm and enriched at the cortex and near the chromosomes. Knockdown of FLNA impaired meiotic asymmetric division and spindle migration with a decrease in the amount of cytoplasmic actin mesh and cortical actin levels. Moreover, FLNA knockdown reduced the phosphorylation of cofilin and Rho kinase (ROCK) near the spindle. Similar phenotypes, such as decreased filament actin levels, impaired spindle migration and polar body extrusion, were observed when active cofilin (S3A) was overexpressed or ROCK was inhibited. Notably, we found that FLNA and ROCK interacted directly in mouse oocytes. Taken together, our results show that FLNA plays crucial roles in asymmetric division during meiotic maturation by regulating ROCK-cofilin-mediated actin reorganization.-Wang, H., Guo J., Lin, Z., Namgoong, S., Oh, J. S., Kim, N.-H. Filamin A is required for spindle migration and asymmetric division in mouse oocytes.
[Mh] Termos MeSH primário: Divisão Celular/fisiologia
Filaminas/metabolismo
Regulação da Expressão Gênica no Desenvolvimento/fisiologia
Oócitos/fisiologia
Fuso Acromático/fisiologia
[Mh] Termos MeSH secundário: Fatores de Despolimerização de Actina/genética
Fatores de Despolimerização de Actina/metabolismo
Actinas/metabolismo
Animais
Clonagem Molecular
Citoplasma/química
Feminino
Filaminas/genética
Técnicas de Silenciamento de Genes
Camundongos
Oócitos/citologia
Transporte Proteico
Quinases Associadas a rho/genética
Quinases Associadas a rho/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actin Depolymerizing Factors); 0 (Actins); 0 (Filamins); EC 2.7.11.1 (rho-Associated Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170511
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201700056R


  9 / 1084 MEDLINE  
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[PMID]:28428218
[Au] Autor:Berrou E; Adam F; Lebret M; Planche V; Fergelot P; Issertial O; Coupry I; Bordet JC; Nurden P; Bonneau D; Colin E; Goizet C; Rosa JP; Bryckaert M
[Ad] Endereço:From the INSERM UMR_S 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France (E.B., F.A., M.L., V.P., O.I., J.-P.R., M.B.); INSERM UMR_S 1211, Université de Bordeaux, CHU Bordeaux UNIV EA 4576, Place Aurélie Raba-Léon, France (P.F., I.C., C.G.); CHU Bordeaux, Centre de Référ
[Ti] Título:Gain-of-Function Mutation in Filamin A Potentiates Platelet Integrin α ß Activation.
[So] Source:Arterioscler Thromb Vasc Biol;37(6):1087-1097, 2017 Jun.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Dominant mutations of the X-linked filamin A ( ) gene are responsible for filaminopathies A, which are rare disorders including brain periventricular nodular heterotopia, congenital intestinal pseudo-obstruction, cardiac valves or skeleton malformations, and often macrothrombocytopenia. APPROACH AND RESULTS: We studied a male patient with periventricular nodular heterotopia and congenital intestinal pseudo-obstruction, his unique X-linked allele carrying a stop codon mutation resulting in a 100-amino acid-long FLNa C-terminal extension (NP_001447.2: ). Platelet counts were normal, with few enlarged platelets. FLNa was detectable in all platelets but at 30% of control levels. Surprisingly, all platelet functions were significantly upregulated, including platelet aggregation and secretion, as induced by ADP, collagen, or von Willebrand factor in the presence of ristocetin, as well as thrombus formation in blood flow on a collagen or on a von Willebrand factor matrix. Most importantly, patient platelets stimulated with ADP exhibited a marked increase in α ß integrin activation and a parallel increase in talin recruitment to ß , contrasting with normal Rap1 activation. These results are consistent with the mutant FLNa affecting the last step of α ß activation. Overexpression of mutant FLNa in the HEL megakaryocytic cell line correlated with an increase (compared with wild-type FLNa) in PMA-induced fibrinogen binding to and in talin and kindlin-3 recruitment by α ß . CONCLUSIONS: Altogether, our results are consistent with a less binding of mutant FLNa to ß and the facilitated recruitment of talin by ß on platelet stimulation, explaining the increased α ß activation and the ensuing gain-of-platelet functions.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Filaminas/genética
Integrina alfa2/sangue
Integrina beta3/sangue
Pseudo-Obstrução Intestinal/genética
Mutação
Heterotopia Nodular Periventricular/genética
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
[Mh] Termos MeSH secundário: Adulto
Plaquetas/ultraestrutura
Linhagem Celular
Análise Mutacional de DNA
Filaminas/sangue
Predisposição Genética para Doença
Hereditariedade
Seres Humanos
Pseudo-Obstrução Intestinal/sangue
Pseudo-Obstrução Intestinal/diagnóstico
Masculino
Heterotopia Nodular Periventricular/sangue
Heterotopia Nodular Periventricular/diagnóstico
Fenótipo
Ativação Plaquetária
Testes de Função Plaquetária
Ligação Proteica
Transdução de Sinais
Talina/sangue
Proteínas de Ligação a Telômeros/sangue
Transfecção
Fator de von Willebrand/metabolismo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FLNA protein, human); 0 (Filamins); 0 (ITGA2B protein, human); 0 (ITGB3 protein, human); 0 (Integrin alpha2); 0 (Integrin beta3); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (TERF2IP protein, human); 0 (Talin); 0 (Telomere-Binding Proteins); 0 (von Willebrand Factor)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170620
[Lr] Data última revisão:
170620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309337


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[PMID]:28356264
[Au] Autor:Gómez J; Lorca R; Reguero JR; Morís C; Martín M; Tranche S; Alonso B; Iglesias S; Alvarez V; Díaz-Molina B; Avanzas P; Coto E
[Ad] Endereço:From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Univers
[Ti] Título:Screening of the Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.
[So] Source:Circ Cardiovasc Genet;10(2), 2017 Apr.
[Is] ISSN:1942-3268
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Recent exome sequencing studies identified filamin C ( ) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of candidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes. METHODS AND RESULTS: A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the , , , , , , , , and genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20 candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported ( =0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign. CONCLUSIONS: We provide a compelling evidence of the involvement of in the development of HCM. Most of the variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.
[Mh] Termos MeSH primário: Cardiomiopatia Hipertrófica/genética
Filaminas/genética
Penetrância
[Mh] Termos MeSH secundário: Estudos de Coortes
Feminino
Testes Genéticos
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FLNC protein, human); 0 (Filamins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170501
[Lr] Data última revisão:
170501
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170331
[St] Status:MEDLINE



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