A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disorder of vascular development. Common manifestations include epistaxis, telangiectasias and arteriovenous malformations in multiple organs. Different deletions or nonsense mutations have been described in the ENG (HHT1) or ACVRL1/ALK1 (HHT2) g...

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Autores: Errasti, Suriel, Peñalva, Mercedes, Recio-Poveda, Lucía, Vilches, Susana, Casado-Vela, Juan, Pérez Pérez, Julián, Botella, Luisa María, Albiñana, Virginia, Cuesta, Ángel M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/271607
Acceso en línea:http://hdl.handle.net/10261/271607
Access Level:acceso abierto
Palabra clave:ACVRL1/ALK1
Hereditary hemorrhagic telangiectasia
Splicing mutation
Osler-Weber-Rendu disease
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spelling A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2Errasti, SurielPeñalva, MercedesRecio-Poveda, LucíaVilches, SusanaCasado-Vela, JuanPérez Pérez, JuliánBotella, Luisa MaríaAlbiñana, VirginiaCuesta, Ángel M.ACVRL1/ALK1Hereditary hemorrhagic telangiectasiaSplicing mutationOsler-Weber-Rendu diseaseHereditary Hemorrhagic Telangiectasia (HHT) is a rare disorder of vascular development. Common manifestations include epistaxis, telangiectasias and arteriovenous malformations in multiple organs. Different deletions or nonsense mutations have been described in the ENG (HHT1) or ACVRL1/ALK1 (HHT2) genes, all affecting endothelial homeostasis. A novel mutation in ACVRL1/ALK1 has been identified in a Peruvian family with a clinical history compatible to HHT. Subsequently, 23 DNA samples from oral exchanges (buccal swaps) of the immediate family members were analyzed together with their clinical histories. A routine cDNA PCR followed by comparative DNA sequencing between the founder and another healthy family member showed the presence of the aforementioned specific mutation. The single mutation detected (c.525 + 1G > T) affects the consensus splice junction immediately after exon 4, provokes anomalous splicing and leads to the inclusion of intron IV between exons 4 and 5 in the ACVRL1/ALK1 mRNA and, therefore, to ALK1 haploinsufficiency. Complete sequencing determined that 10 of the 25 family members analyzed were affected by the same mutation. Notably, the approach described in this report could be used as a diagnostic technique, easily incorporated in clinical practice in developing countries and easily extrapolated to other patients carrying such a mutation.This research was funded by MINECO (Ministry of Economy of Spain), grant number SAF2017-83351R, and by MICINN (Ministry of Science and Innovation of Spain), grant number PID2020-115371RB-I00. LR-P was the recipient of a contract from an internal project of CSIC (PIE201820E073).Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Consejo Superior de Investigaciones Científicas (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/271607reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83351-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115371RB-I00https://doi.org/10.3390/jcm11113053Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2716072026-05-22T06:33:51Z
dc.title.none.fl_str_mv A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2
title A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2
spellingShingle A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2
Errasti, Suriel
ACVRL1/ALK1
Hereditary hemorrhagic telangiectasia
Splicing mutation
Osler-Weber-Rendu disease
title_short A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2
title_full A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2
title_fullStr A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2
title_full_unstemmed A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2
title_sort A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2
dc.creator.none.fl_str_mv Errasti, Suriel
Peñalva, Mercedes
Recio-Poveda, Lucía
Vilches, Susana
Casado-Vela, Juan
Pérez Pérez, Julián
Botella, Luisa María
Albiñana, Virginia
Cuesta, Ángel M.
author Errasti, Suriel
author_facet Errasti, Suriel
Peñalva, Mercedes
Recio-Poveda, Lucía
Vilches, Susana
Casado-Vela, Juan
Pérez Pérez, Julián
Botella, Luisa María
Albiñana, Virginia
Cuesta, Ángel M.
author_role author
author2 Peñalva, Mercedes
Recio-Poveda, Lucía
Vilches, Susana
Casado-Vela, Juan
Pérez Pérez, Julián
Botella, Luisa María
Albiñana, Virginia
Cuesta, Ángel M.
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Consejo Superior de Investigaciones Científicas (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv ACVRL1/ALK1
Hereditary hemorrhagic telangiectasia
Splicing mutation
Osler-Weber-Rendu disease
topic ACVRL1/ALK1
Hereditary hemorrhagic telangiectasia
Splicing mutation
Osler-Weber-Rendu disease
description Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disorder of vascular development. Common manifestations include epistaxis, telangiectasias and arteriovenous malformations in multiple organs. Different deletions or nonsense mutations have been described in the ENG (HHT1) or ACVRL1/ALK1 (HHT2) genes, all affecting endothelial homeostasis. A novel mutation in ACVRL1/ALK1 has been identified in a Peruvian family with a clinical history compatible to HHT. Subsequently, 23 DNA samples from oral exchanges (buccal swaps) of the immediate family members were analyzed together with their clinical histories. A routine cDNA PCR followed by comparative DNA sequencing between the founder and another healthy family member showed the presence of the aforementioned specific mutation. The single mutation detected (c.525 + 1G > T) affects the consensus splice junction immediately after exon 4, provokes anomalous splicing and leads to the inclusion of intron IV between exons 4 and 5 in the ACVRL1/ALK1 mRNA and, therefore, to ALK1 haploinsufficiency. Complete sequencing determined that 10 of the 25 family members analyzed were affected by the same mutation. Notably, the approach described in this report could be used as a diagnostic technique, easily incorporated in clinical practice in developing countries and easily extrapolated to other patients carrying such a mutation.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/271607
url http://hdl.handle.net/10261/271607
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83351-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115371RB-I00
https://doi.org/10.3390/jcm11113053
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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