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dc.contributor.authorBorràs N
dc.contributor.authorOrriols G
dc.contributor.authorBatlle Fonrodona, Francisco Javier 
dc.contributor.authorPerez Rodriguez, Almudena
dc.contributor.authorFidalgo T
dc.contributor.authorMartinho P
dc.contributor.authorLópez Fernández, María Fernanda 
dc.contributor.authorRodríguez Trillo, Angela
dc.contributor.authorLourés Fraga, Esther 
dc.contributor.authorParra R
dc.contributor.authorAltisent C
dc.contributor.authorCid AR
dc.contributor.authorBonanad S
dc.contributor.authorCabrera N
dc.contributor.authorMoret A
dc.contributor.authorMingot-Castellano ME
dc.contributor.authorNavarro N
dc.contributor.authorPérez-Montes R
dc.contributor.authorMarcellini S
dc.contributor.authorMoreto A
dc.contributor.authorHerrero S
dc.contributor.authorSoto I
dc.contributor.authorFernández-Mosteirín N
dc.contributor.authorJiménez-Yuste V
dc.contributor.authorAlonso N
dc.contributor.authorde Andrés y Jacob, Aurora
dc.contributor.authorFontanes Trabazo, Emilia
dc.contributor.authorCampos R
dc.contributor.authorPaloma MJ
dc.contributor.authorBermejo N
dc.contributor.authorBerrueco R
dc.contributor.authorMateo J
dc.contributor.authorArribalzaga K
dc.contributor.authorMarco P
dc.contributor.authorPalomo Á
dc.contributor.authorCastro Quismondo N
dc.contributor.authorIñigo B
dc.contributor.authorNieto MDM
dc.contributor.authorVidal R
dc.contributor.authorMartínez MP
dc.contributor.authorAguinaco R
dc.contributor.authorTenorio JM
dc.contributor.authorAlbors Ferreiro, Manuel 
dc.contributor.authorGarcía-Frade J
dc.contributor.authorRodríguez-Huerta AM
dc.contributor.authorCuesta J
dc.contributor.authorRodríguez-González R
dc.contributor.authorGarcía-Candel F
dc.contributor.authorDobón M
dc.contributor.authorAguilar C
dc.contributor.authorVidal F
dc.contributor.authorCorrales I
dc.date.accessioned2021-06-07T12:57:12Z
dc.date.available2021-06-07T12:57:12Z
dc.date.issued2019
dc.identifier.issn0390-6078
dc.identifier.otherhttps://www.ncbi.nlm.nih.gov/pubmed/30361419es
dc.identifier.urihttp://hdl.handle.net/20.500.11940/15003
dc.description.abstractLarge studies in von Willebrand disease patients, including Spanish and Portuguese registries, led to the identification of >250 different mutations. It is a challenge to determine the pathogenic effect of potential splice site mutations on VWF mRNA. This study aimed to elucidate the true effects of 18 mutations on VWF mRNA processing, investigate the contribution of next-generation sequencing to in vivo mRNA study in von Willebrand disease, and compare the findings with in silico prediction. RNA extracted from patient platelets and leukocytes was amplified by RT-PCR and sequenced using Sanger and next generation sequencing techniques. Eight mutations affected VWF splicing: c.1533+1G>A, c.5664+2T>C and c.546G>A (p.=) prompted exon skipping; c.3223-7_3236dup and c.7082-2A>G resulted in activation of cryptic sites; c.3379+1G>A and c.7437G>A) demonstrated both molecular pathogenic mechanisms simultaneously; and the p.Cys370Tyr missense mutation generated two aberrant transcripts. Of note, the complete effect of three mutations was provided by next generation sequencing alone because of low expression of the aberrant transcripts. In the remaining 10 mutations, no effect was elucidated in the experiments. However, the differential findings obtained in platelets and leukocytes provided substantial evidence that four of these would have an effect on VWF levels. In this first report using next generation sequencing technology to unravel the effects of VWF mutations on splicing, the technique yielded valuable information. Our data bring to light the importance of studying the effect of synonymous and missense mutations on VWF splicing to improve the current knowledge of the molecular mechanisms behind von Willebrand disease. clinicaltrials.gov identifier:02869074.en
dc.language.isoenges
dc.subject.meshBase Sequence*
dc.subject.meshvon Willebrand Factor*
dc.subject.meshvon Willebrand Diseases*
dc.subject.meshExons*
dc.subject.meshIntrons*
dc.subject.meshRNA*
dc.subject.meshLeukocytes*
dc.subject.meshGene Silencing*
dc.subject.meshGenotype*
dc.subject.meshMutation*
dc.subject.meshComputational Biology*
dc.subject.meshBlood Platelets*
dc.subject.meshHumans*
dc.subject.meshRNA Splicing*
dc.subject.meshHigh-Throughput Nucleotide Sequencing*
dc.subject.meshRNA Splice Sites*
dc.subject.meshGene Frequency*
dc.subject.meshAlleles*
dc.titleUnraveling the effect of silent, intronic and missense mutations on VWF splicing: contribution of next generation sequencing in the study of mRNAen
dc.typeArtigoes
dc.authorsophosBorràs N
dc.authorsophosOrriols G
dc.authorsophosBatlle J
dc.authorsophosPérez-Rodríguez A
dc.authorsophosFidalgo T
dc.authorsophosMartinho P
dc.authorsophosLópez-Fernández MF
dc.authorsophosRodríguez-Trillo Á
dc.authorsophosLourés E
dc.authorsophosParra R
dc.authorsophosAltisent C
dc.authorsophosCid AR
dc.authorsophosBonanad S
dc.authorsophosCabrera N
dc.authorsophosMoret A
dc.authorsophosMingot-Castellano ME
dc.authorsophosNavarro N
dc.authorsophosPérez-Montes R
dc.authorsophosMarcellini S
dc.authorsophosMoreto A
dc.authorsophosHerrero S
dc.authorsophosSoto I
dc.authorsophosFernández-Mosteirín N
dc.authorsophosJiménez-Yuste V
dc.authorsophosAlonso N
dc.authorsophosde Andrés-Jacob A
dc.authorsophosFontanes E
dc.authorsophosCampos R
dc.authorsophosPaloma MJ
dc.authorsophosBermejo N
dc.authorsophosBerrueco R
dc.authorsophosMateo J
dc.authorsophosArribalzaga K
dc.authorsophosMarco P
dc.authorsophosPalomo Á
dc.authorsophosCastro Quismondo N
dc.authorsophosIñigo B
dc.authorsophosNieto MDM
dc.authorsophosVidal R
dc.authorsophosMartínez MP
dc.authorsophosAguinaco R
dc.authorsophosTenorio JM
dc.authorsophosFerreiro M
dc.authorsophosGarcía-Frade J
dc.authorsophosRodríguez-Huerta AM
dc.authorsophosCuesta J
dc.authorsophosRodríguez-González R
dc.authorsophosGarcía-Candel F
dc.authorsophosDobón M
dc.authorsophosAguilar C
dc.authorsophosVidal F
dc.authorsophosCorrales I
dc.identifier.doi10.3324/haematol.2018.203166
dc.identifier.pmid30361419
dc.identifier.sophos28266
dc.issue.number3es
dc.journal.titleHaematologicaes
dc.organizationÁrea Sanitaria de A Coruña e Cee/Complexo Hospitalario Universitario A Coruña/Hematoloxía clínicaes
dc.organizationÁrea Sanitaria de Santiago de Compostela e Barbanza/Complexo Hospitalario Universitario de Santiago/Hematoloxía clínicaes
dc.organizationÁrea Sanitaria de Lugo, A Mariña e Monforte de Lemos/Hospital Universitario Lucus Augusti/Hematoloxía clínicaes
dc.organizationÁrea Sanitaria de Pontevedra e O Salnés/Complexo Hospitalario Universitario de Pontevedra/Hematoloxía clínicaes
dc.organizationSERGAS/Área Sanitaria de A Coruña e Cee/INIBIC.- Instituto de Investigación Biomédicaes
dc.organizationServizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI):EOXI de A Coruña - Complexo Hospitalario Universitario de A Coruña::Hematoloxía clínicaes
dc.organizationServizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI):EOXI de Santiago de Compostela - Complexo Hospitalario Universitario de Santiago de Compostela::Hematoloxía clínicaes
dc.organizationServizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI):EOXI de Lugo, Cervo e Monforte de lemos - Complexo Hospitalario Universitario Lucus Augusti::Hematoloxía clínicaes
dc.organizationServizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::EOXI de Pontevedra e O Salnés - Complexo Hospitalario Universitario de Pontevedra::Hematoloxía clínicaes
dc.organizationServizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::Instituto de Investigación Biomédica da Coruña (INIBIC)es
dc.organizationCHUACes
dc.organizationHematoloxía clínicaes
dc.organizationHematoloxía clínicaes
dc.organizationCHUSes
dc.organizationHULAes
dc.organizationCHUPes
dc.organizationINIBICes
dc.page.initial587es
dc.page.final598es
dc.relation.publisherversionhttps://haematologica.org/article/download/8816/62194es
dc.rights.accessRightsembargoedAccesses
dc.subject.decssitios de empalme del ARN*
dc.subject.decsmutación*
dc.subject.decsfrecuencia génica*
dc.subject.decssecuenciación de nucleótidos de alto rendimiento*
dc.subject.decsfactor de von Willebrand*
dc.subject.decsexones*
dc.subject.decsalelos*
dc.subject.decsenfermedades de von Willebrand*
dc.subject.decsARN*
dc.subject.decssecuencia de bases*
dc.subject.decsbiología computacional*
dc.subject.decssilenciamiento génico*
dc.subject.decsgenotipo*
dc.subject.decsempalme de ARN*
dc.subject.decshumanos*
dc.subject.decsleucocitos*
dc.subject.decsintrones*
dc.subject.decsplaquetas*
dc.typefidesArtículo Científico (incluye Original, Original breve, Revisión Sistemática y Meta-análisis)es
dc.typesophosArtículo Originales
dc.volume.number104es


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