Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.

Detalles Bibliográficos
Autores: Lara, Beatriz, Martínez-Santiago, María Teresa, Blanco, Ignacio, Hernández-Moro, Cristina, Velasco, Eladio, Ferrarotti, Ilaria, Rodríguez-Frías, Francisco, Pérez, Laura, Vazquez, Irene, Alonso, Javier, Posada, Manuel, Martínez-Delgado, Beatriz
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/107555
Acceso en línea:http://hdl.handle.net/10261/107555
Access Level:acceso abierto
Palabra clave:Alpha-1 antitrypsin
Allelic variants
Null alleles
QO alleles
Splicing
Minigenes
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spelling Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadridLara, BeatrizMartínez-Santiago, María TeresaBlanco, IgnacioHernández-Moro, CristinaVelasco, EladioFerrarotti, IlariaRodríguez-Frías, FranciscoPérez, LauraVazquez, IreneAlonso, JavierPosada, ManuelMartínez-Delgado, BeatrizAlpha-1 antitrypsinAllelic variantsNull allelesQO allelesSplicingMinigenesThis is an Open Access article distributed under the terms of the Creative Commons Attribution License.[Background]: Severe Alpha-1 Antitrypsin (AAT) deficiency is a hereditary condition caused by mutations in the SERPINA1 gene, which predisposes to lung emphysema and liver disease. It is usually related to PI*Z alleles, and less frequent to rare and null (QO) alleles. Null-AAT alleles represent the end of a continuum of variants associated with profound AAT deficiency and extremely increased risk of emphysema. [Methods]: A family with severe AAT deficiency was analyzed to achieve genetic diagnosis. The complete exons and introns of the SERPINA1 gene were sequenced and transcriptional analysis by RT-PCR was performed to characterize the effect of splicing variants found in the patients. In addition, a minigene MGserpa1_ex1b-1c was cloned into the pSAD vector to in vitro investigate the independent impact of variants on splicing process.[Results]: We report a new identified null allele (PI*QOMadrid) in two adult siblings with practically no detectable serum AAT. The PI*QOMadrid allele consist of a duplication of the thymine (T) in position +2 of the donor splice site of exon 1C (+2dupT). In these two subjects, PI*QOMadrid occurred in compound heterozygote combination with the previously described variant PI*QOPorto. Both QOMadrid and QOPorto variants are located very close together in a regulatory region of the SERPINA1 gene. Analysis of transcripts revealed that QOMadrid variant prevented the expression of transcripts from exon 1C, and then normally spliced RNA products are not expected in the liver of these patients. In addition, aberrant splicing patterns of both variants were clearly distinguished and quantified by functional in vitro assays lending further support to their pathogenicity. [Conclusion]: Finding pathogenic mutations in non-coding regions of the SERPINA1 highlight the importance that regulatory regions might have in the disease. Regulatory regions should be seriously considered in discordant cases with severe AAT deficiency where no coding mutations were found.This work has been partially funded by the Instituto de Salud Carlos III grants TPY1250/12 (BMD) and PI13/1749 (EAV) (Spanish Ministry of Economy and Competitiveness) and BIO/VA08/13 (Consejería de Sanidad, Junta de Castilla y León). CHM was supported by a fellowship from Fundación Villalar (Cortes de Castilla y León, Spain).Peer reviewedBioMed CentralMinisterio de Economía y Competitividad (España)Junta de Castilla y LeónFundación VillalarConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201420142014info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/107555reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1186/s12931-014-0125-ySíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1075552026-05-22T06:33:51Z
dc.title.none.fl_str_mv Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
title Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
spellingShingle Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
Lara, Beatriz
Alpha-1 antitrypsin
Allelic variants
Null alleles
QO alleles
Splicing
Minigenes
title_short Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
title_full Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
title_fullStr Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
title_full_unstemmed Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
title_sort Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
dc.creator.none.fl_str_mv Lara, Beatriz
Martínez-Santiago, María Teresa
Blanco, Ignacio
Hernández-Moro, Cristina
Velasco, Eladio
Ferrarotti, Ilaria
Rodríguez-Frías, Francisco
Pérez, Laura
Vazquez, Irene
Alonso, Javier
Posada, Manuel
Martínez-Delgado, Beatriz
author Lara, Beatriz
author_facet Lara, Beatriz
Martínez-Santiago, María Teresa
Blanco, Ignacio
Hernández-Moro, Cristina
Velasco, Eladio
Ferrarotti, Ilaria
Rodríguez-Frías, Francisco
Pérez, Laura
Vazquez, Irene
Alonso, Javier
Posada, Manuel
Martínez-Delgado, Beatriz
author_role author
author2 Martínez-Santiago, María Teresa
Blanco, Ignacio
Hernández-Moro, Cristina
Velasco, Eladio
Ferrarotti, Ilaria
Rodríguez-Frías, Francisco
Pérez, Laura
Vazquez, Irene
Alonso, Javier
Posada, Manuel
Martínez-Delgado, Beatriz
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Junta de Castilla y León
Fundación Villalar
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Alpha-1 antitrypsin
Allelic variants
Null alleles
QO alleles
Splicing
Minigenes
topic Alpha-1 antitrypsin
Allelic variants
Null alleles
QO alleles
Splicing
Minigenes
description This is an Open Access article distributed under the terms of the Creative Commons Attribution License.
publishDate 2014
dc.date.none.fl_str_mv 2014
2014
2014
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/10261/107555
url http://hdl.handle.net/10261/107555
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1186/s12931-014-0125-y
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
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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