New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in the SERPINA1 (Serpin family A member 1) gene. The Pi*S (Glu264Val) is one of the most frequent deficient alleles of AATD, showing high incidence in the Iberian Peninsula....

Descripción completa

Detalles Bibliográficos
Autores: Matamala, Nerea, Gomez-Mariano, Gema Maria, Perez, Jose Antonio, Baladron-Jimenez, Beatriz Isabel, Torres-Durán, María, Michel, Francisco Javier, Saez, Raquel, Hernández-Pérez, Jose María, Belmonte, Irene, Rodriguez-Frias, Francisco, Blanco, Ignacio, Strnad, Pavel, Janciauskiene, Sabina, Martinez-Delgado, Beatriz
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17264
Acceso en línea:http://hdl.handle.net/20.500.12105/17264
Access Level:acceso abierto
Palabra clave:Adult
Alleles
DNA Mutational Analysis
Female
Gene Frequency
Genotype
Humans
Male
Middle Aged
Mutation
Phenotype
alpha 1-Antitrypsin
alpha 1-Antitrypsin Deficiency
id ES_41baa2a1c69de74f434d7ae45fa8b7cb
oai_identifier_str oai:repisalud.isciii.es:20.500.12105/17264
network_acronym_str ES
network_name_str España
repository_id_str
spelling New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin DeficiencyMatamala, NereaGomez-Mariano, Gema MariaPerez, Jose AntonioBaladron-Jimenez, Beatriz IsabelTorres-Durán, MaríaMichel, Francisco JavierSaez, RaquelHernández-Pérez, Jose MaríaBelmonte, IreneRodriguez-Frias, FranciscoBlanco, IgnacioStrnad, PavelJanciauskiene, SabinaMartinez-Delgado, BeatrizAdultAllelesDNA Mutational AnalysisFemaleGene FrequencyGenotypeHumansMaleMiddle AgedMutationPhenotypealpha 1-Antitrypsinalpha 1-Antitrypsin DeficiencyAlpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in the SERPINA1 (Serpin family A member 1) gene. The Pi*S (Glu264Val) is one of the most frequent deficient alleles of AATD, showing high incidence in the Iberian Peninsula. Herein, we describe two new alleles carrying an S mutation but producing a null phenotype: QOVigo and QOAachen. The new alleles were identified by sequencing the SERPINA1 gene in three patients who had lower AAT serum levels than expected for the initial genotype. These alleles are the result of combined mutations in cis in a PI*S allele. Sequencing detected the S mutation in cis with Tyr138Cys (S+Tyr138Cys) in two patients, whereas a third one had the S mutation in cis with Pro391Thr variant (S+Pro391Thr). When expressed in a cellular model, these variants caused strong AAT polymerization and very low AAT secretion to almost undetectable levels. The isoelectric focusing method for plasma AAT phenotyping did not show AAT protein encoded by the novel mutant alleles, behaving as null. We called these alleles PI*S-plus because the S variant was phased with another variant conferring more aggressive characteristics to the allele. The current data demonstrate that the clinical variability observed in AATD can be explained by additional genetic variation, such as dual cis-acting variants in the SERPINA1 gene. The possible existence of other unrevealed variants combined in the PI*S alleles should be considered to improve the genetic diagnosis of the patients.American Thoracic Society (ATS)Instituto de Salud Carlos IIIDeutsche Forschungsgemeinschaft (Alemania)20242024-01-2320202020-10-0120202020-10-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12105/17264reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/172642026-06-12T12:43:37Z
dc.title.none.fl_str_mv New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency
title New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency
spellingShingle New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency
Matamala, Nerea
Adult
Alleles
DNA Mutational Analysis
Female
Gene Frequency
Genotype
Humans
Male
Middle Aged
Mutation
Phenotype
alpha 1-Antitrypsin
alpha 1-Antitrypsin Deficiency
title_short New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency
title_full New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency
title_fullStr New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency
title_full_unstemmed New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency
title_sort New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency
dc.creator.none.fl_str_mv Matamala, Nerea
Gomez-Mariano, Gema Maria
Perez, Jose Antonio
Baladron-Jimenez, Beatriz Isabel
Torres-Durán, María
Michel, Francisco Javier
Saez, Raquel
Hernández-Pérez, Jose María
Belmonte, Irene
Rodriguez-Frias, Francisco
Blanco, Ignacio
Strnad, Pavel
Janciauskiene, Sabina
Martinez-Delgado, Beatriz
author Matamala, Nerea
author_facet Matamala, Nerea
Gomez-Mariano, Gema Maria
Perez, Jose Antonio
Baladron-Jimenez, Beatriz Isabel
Torres-Durán, María
Michel, Francisco Javier
Saez, Raquel
Hernández-Pérez, Jose María
Belmonte, Irene
Rodriguez-Frias, Francisco
Blanco, Ignacio
Strnad, Pavel
Janciauskiene, Sabina
Martinez-Delgado, Beatriz
author_role author
author2 Gomez-Mariano, Gema Maria
Perez, Jose Antonio
Baladron-Jimenez, Beatriz Isabel
Torres-Durán, María
Michel, Francisco Javier
Saez, Raquel
Hernández-Pérez, Jose María
Belmonte, Irene
Rodriguez-Frias, Francisco
Blanco, Ignacio
Strnad, Pavel
Janciauskiene, Sabina
Martinez-Delgado, Beatriz
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Deutsche Forschungsgemeinschaft (Alemania)
dc.subject.none.fl_str_mv Adult
Alleles
DNA Mutational Analysis
Female
Gene Frequency
Genotype
Humans
Male
Middle Aged
Mutation
Phenotype
alpha 1-Antitrypsin
alpha 1-Antitrypsin Deficiency
topic Adult
Alleles
DNA Mutational Analysis
Female
Gene Frequency
Genotype
Humans
Male
Middle Aged
Mutation
Phenotype
alpha 1-Antitrypsin
alpha 1-Antitrypsin Deficiency
description Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in the SERPINA1 (Serpin family A member 1) gene. The Pi*S (Glu264Val) is one of the most frequent deficient alleles of AATD, showing high incidence in the Iberian Peninsula. Herein, we describe two new alleles carrying an S mutation but producing a null phenotype: QOVigo and QOAachen. The new alleles were identified by sequencing the SERPINA1 gene in three patients who had lower AAT serum levels than expected for the initial genotype. These alleles are the result of combined mutations in cis in a PI*S allele. Sequencing detected the S mutation in cis with Tyr138Cys (S+Tyr138Cys) in two patients, whereas a third one had the S mutation in cis with Pro391Thr variant (S+Pro391Thr). When expressed in a cellular model, these variants caused strong AAT polymerization and very low AAT secretion to almost undetectable levels. The isoelectric focusing method for plasma AAT phenotyping did not show AAT protein encoded by the novel mutant alleles, behaving as null. We called these alleles PI*S-plus because the S variant was phased with another variant conferring more aggressive characteristics to the allele. The current data demonstrate that the clinical variability observed in AATD can be explained by additional genetic variation, such as dual cis-acting variants in the SERPINA1 gene. The possible existence of other unrevealed variants combined in the PI*S alleles should be considered to improve the genetic diagnosis of the patients.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-10-01
2020
2020-10-01
2024
2024-01-23
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/20.500.12105/17264
url http://hdl.handle.net/20.500.12105/17264
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/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
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Thoracic Society (ATS)
publisher.none.fl_str_mv American Thoracic Society (ATS)
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
_version_ 1869406874532577280
score 15,812429

Similares en LA Referencia