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 en...

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Autores: Lara, Beatriz, Varela Martinez, Maria del Carmen, Blanco, Ignacio, Hernández-Moro, Cristina, Velasco, Eladio A, Ferrarotti, Ilaria, Rodriguez-Frias, Francisco, Perez, Laura, Vazquez-Dominguez, Irene, Alonso, Javier, Posada De la Paz, Manuel, Martinez-Delgado, Beatriz
Formato: artículo
Fecha de publicación:2014
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/4827
Acesso em linha:http://hdl.handle.net/20.500.12105/4827
Access Level:acceso abierto
Palavra-chave:Alpha-1 antitrypsin
Allelic variants
Null alleles
QO alleles, Splicing, Minigenes
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repository_id_str
spelling Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadridLara, BeatrizVarela Martinez, Maria del CarmenBlanco, IgnacioHernández-Moro, CristinaVelasco, Eladio AFerrarotti, IlariaRodriguez-Frias, FranciscoPerez, LauraVazquez-Dominguez, IreneAlonso, JavierPosada De la Paz, ManuelMartinez-Delgado, BeatrizAlpha-1 antitrypsinAllelic variantsNull allelesQO alleles, Splicing, MinigenesBackground: 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.BioMed Central (BMC)Instituto de Salud Carlos IIIMinisterio de Economía y Competitividad (España)Junta de Castilla y León (España)20172017-09-0420142014-10-0720142014-10-07research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/4827reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengES PI13 1749open accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/48272026-06-12T12:43:37Z
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
Varela Martinez, Maria del Carmen
Blanco, Ignacio
Hernández-Moro, Cristina
Velasco, Eladio A
Ferrarotti, Ilaria
Rodriguez-Frias, Francisco
Perez, Laura
Vazquez-Dominguez, Irene
Alonso, Javier
Posada De la Paz, Manuel
Martinez-Delgado, Beatriz
author Lara, Beatriz
author_facet Lara, Beatriz
Varela Martinez, Maria del Carmen
Blanco, Ignacio
Hernández-Moro, Cristina
Velasco, Eladio A
Ferrarotti, Ilaria
Rodriguez-Frias, Francisco
Perez, Laura
Vazquez-Dominguez, Irene
Alonso, Javier
Posada De la Paz, Manuel
Martinez-Delgado, Beatriz
author_role author
author2 Varela Martinez, Maria del Carmen
Blanco, Ignacio
Hernández-Moro, Cristina
Velasco, Eladio A
Ferrarotti, Ilaria
Rodriguez-Frias, Francisco
Perez, Laura
Vazquez-Dominguez, Irene
Alonso, Javier
Posada De la Paz, Manuel
Martinez-Delgado, Beatriz
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Ministerio de Economía y Competitividad (España)
Junta de Castilla y León (España)
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 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
2014-10-07
2014
2014-10-07
2017
2017-09-04
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/4827
url http://hdl.handle.net/20.500.12105/4827
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv ES PI13 1749
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BioMed Central (BMC)
publisher.none.fl_str_mv BioMed Central (BMC)
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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