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

[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...

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Authors: Lara Gallego, Beatriz, Martínez, María Teresa, Blanco, Ignacio, Hernández, Cristina, Velasco, Eladio, Ferrarotti, Ilaria, Rodríguez, Francisco, Perez, Laura, Vazquez, Irene, Alonso, Javier, Posada, Manuel, Martínez-Delgado, Beatriz
Format: article
Status:Published version
Publication Date:2014
Country:España
Institution:Universitat de Lleida (UdL)
Repository:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/65054
Online Access:https://doi.org/10.1186/s12931-014-0125-y
http://hdl.handle.net/10459.1/65054
Access Level:Open access
Keyword:Alpha-1 antitrypsin
Allelic variants
Null alleles
QO alleles
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spelling Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadridLara Gallego, BeatrizMartínez, María TeresaBlanco, IgnacioHernández, CristinaVelasco, EladioFerrarotti, IlariaRodríguez, FranciscoPerez, LauraVazquez, IreneAlonso, JavierPosada, ManuelMartínez-Delgado, BeatrizAlpha-1 antitrypsinAllelic variantsNull allelesQO alleles[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). We thank collaborators from the REDAAT (Spanish Registry of Alpha-1 Antitrypsin deficiency patients) and all members of the Human Genetics Area of the ISCIII for their support.BioMed Central2014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1186/s12931-014-0125-yhttp://hdl.handle.net/10459.1/65054reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésReproducció del document publicat a https://doi.org/10.1186/s12931-014-0125-yRespiratory Research, 2014, vol. 15, art. 125cc-by (c) Beatriz Lara et al., 2015info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/4.0/oai:repositori.udl.cat:10459.1/650542026-06-24T12:42:17Z
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 Gallego, Beatriz
Alpha-1 antitrypsin
Allelic variants
Null alleles
QO alleles
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 Gallego, Beatriz
Martínez, María Teresa
Blanco, Ignacio
Hernández, Cristina
Velasco, Eladio
Ferrarotti, Ilaria
Rodríguez, Francisco
Perez, Laura
Vazquez, Irene
Alonso, Javier
Posada, Manuel
Martínez-Delgado, Beatriz
author Lara Gallego, Beatriz
author_facet Lara Gallego, Beatriz
Martínez, María Teresa
Blanco, Ignacio
Hernández, Cristina
Velasco, Eladio
Ferrarotti, Ilaria
Rodríguez, Francisco
Perez, Laura
Vazquez, Irene
Alonso, Javier
Posada, Manuel
Martínez-Delgado, Beatriz
author_role author
author2 Martínez, María Teresa
Blanco, Ignacio
Hernández, Cristina
Velasco, Eladio
Ferrarotti, Ilaria
Rodríguez, Francisco
Perez, Laura
Vazquez, Irene
Alonso, Javier
Posada, Manuel
Martínez-Delgado, Beatriz
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alpha-1 antitrypsin
Allelic variants
Null alleles
QO alleles
topic Alpha-1 antitrypsin
Allelic variants
Null alleles
QO alleles
description [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.
publishDate 2014
dc.date.none.fl_str_mv 2014
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1186/s12931-014-0125-y
http://hdl.handle.net/10459.1/65054
url https://doi.org/10.1186/s12931-014-0125-y
http://hdl.handle.net/10459.1/65054
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a https://doi.org/10.1186/s12931-014-0125-y
Respiratory Research, 2014, vol. 15, art. 125
dc.rights.none.fl_str_mv cc-by (c) Beatriz Lara et al., 2015
info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by (c) Beatriz Lara et al., 2015
https://creativecommons.org/licenses/by/4.0/
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:Repositori Obert UdL
instname:Universitat de Lleida (UdL)
instname_str Universitat de Lleida (UdL)
reponame_str Repositori Obert UdL
collection Repositori Obert UdL
repository.name.fl_str_mv
repository.mail.fl_str_mv
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