Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency
[Background] Mutations in the SERPINA1 gene can result in alpha-1 antitrypsin deficiency (AATD), which may be associated with lung or liver injury. Although the S and Z alleles account for over 95% of cases of AATD, a wide variety of rare variants have been linked to deficiency and dysfunction, whil...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2026 |
| País: | España |
| Recursos: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:dnet:digitalcsic_::c81872047aae2d6f02d88cc460e2f124 |
| Acesso em linha: | http://hdl.handle.net/10261/432047 https://api.elsevier.com/content/abstract/scopus_id/105030840148 |
| Access Level: | acceso abierto |
| Palavra-chave: | Alpha1 antitrypsin deficiency Diagnosis Mutations SERPINA1 |
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Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiencyMatamala, NereaOsaba, LourdesDrobnic, EstrellaGil-Martín, SaraMartín-Galiano, Antonio J.Almadana-Pacheco, VirginiaCazorla, Maria JesúsCosta, FabioSouza-Sokoloski, CarolineÇörtük, MustafaSerra-Fortuny, MireiaOrtiz-de Saracho, JuanLloret-Queraltó, Juan AntonioRodriguez-Lázaro, NuriaMichel-de la Rosa, Francisco JavierRodríguez-Hermosa, Juan LuisSaldaña-Pérez, LeonardoAkıncı, ElifAlonso, JavierBenítez-Buelga, CarlosGómez-Mariano, GemaLópez-Campos, José LuisMartínez-Delgado, BeatrizAlpha1 antitrypsin deficiencyDiagnosisMutationsSERPINA1[Background] Mutations in the SERPINA1 gene can result in alpha-1 antitrypsin deficiency (AATD), which may be associated with lung or liver injury. Although the S and Z alleles account for over 95% of cases of AATD, a wide variety of rare variants have been linked to deficiency and dysfunction, while other variants are associated with normal alpha-1 antitrypsin (AAT) levels and activity. Here, we present the identification and characterization of thirteen rare SERPINA1 variants discovered during the genetic diagnosis of AATD by the Progenika diagnostic network.[Methods] The new variants were identified by sequencing the exons of SERPINA1 gene in cases with discrepancies between AAT serum levels and initial genotyping. In order to determine their pathogenic impact, the variants were expressed in a cellular model and evaluated for AAT secretion, intracellular accumulation and elastase inhibitory activity. In addition, protein structural mapping of the variants and analysis of positioning and residue/atomic contacts were performed.[Results] The in silico and functional in vitro analysis allowed us to classify these AAT variants as six deficient (p.Val234Glu, p.Val242_Pro243insLeu, p.Leu291Phe, p.Ala308Ser, p.Pro393Thr and p.Pro393Arg), one dysfunctional (p.Thr96Ile), three normal (p.Ser71Arg, p.Ala349Pro and p.Asp365Glu) and three null alleles (p.Gln33*, p.Gln285* and p.Leu310Phefs*14).[Conclusions] Functional assays and protein structural information are useful tools in the characterization of novel variants of the SERPINA1 gene. The newly characterized mutations expand the number of SERPINA1 variants with proven pathogenic effects, facilitating the diagnoses of future cases of AATD.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This study was funded by Grifols, manufacturer of an A1AT Genotyping test.Peer reviewedSpringer NatureBioMed CentralConferencia de Rectores de las Universidades EspañolasConsejo Superior de Investigaciones Científicas (España)202620262026info:eu-repo/semantics/articlePublisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/432047https://api.elsevier.com/content/abstract/scopus_id/105030840148reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1186/s12931-025-03486-1https://doi.org/10.1186/s12931-025-03486-1Síinfo:eu-repo/semantics/openAccessoai:dnet:digitalcsic_::c81872047aae2d6f02d88cc460e2f1242026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency |
| title |
Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency |
| spellingShingle |
Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency Matamala, Nerea Alpha1 antitrypsin deficiency Diagnosis Mutations SERPINA1 |
| title_short |
Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency |
| title_full |
Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency |
| title_fullStr |
Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency |
| title_full_unstemmed |
Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency |
| title_sort |
Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency |
| dc.creator.none.fl_str_mv |
Matamala, Nerea Osaba, Lourdes Drobnic, Estrella Gil-Martín, Sara Martín-Galiano, Antonio J. Almadana-Pacheco, Virginia Cazorla, Maria Jesús Costa, Fabio Souza-Sokoloski, Caroline Çörtük, Mustafa Serra-Fortuny, Mireia Ortiz-de Saracho, Juan Lloret-Queraltó, Juan Antonio Rodriguez-Lázaro, Nuria Michel-de la Rosa, Francisco Javier Rodríguez-Hermosa, Juan Luis Saldaña-Pérez, Leonardo Akıncı, Elif Alonso, Javier Benítez-Buelga, Carlos Gómez-Mariano, Gema López-Campos, José Luis Martínez-Delgado, Beatriz |
| author |
Matamala, Nerea |
| author_facet |
Matamala, Nerea Osaba, Lourdes Drobnic, Estrella Gil-Martín, Sara Martín-Galiano, Antonio J. Almadana-Pacheco, Virginia Cazorla, Maria Jesús Costa, Fabio Souza-Sokoloski, Caroline Çörtük, Mustafa Serra-Fortuny, Mireia Ortiz-de Saracho, Juan Lloret-Queraltó, Juan Antonio Rodriguez-Lázaro, Nuria Michel-de la Rosa, Francisco Javier Rodríguez-Hermosa, Juan Luis Saldaña-Pérez, Leonardo Akıncı, Elif Alonso, Javier Benítez-Buelga, Carlos Gómez-Mariano, Gema López-Campos, José Luis Martínez-Delgado, Beatriz |
| author_role |
author |
| author2 |
Osaba, Lourdes Drobnic, Estrella Gil-Martín, Sara Martín-Galiano, Antonio J. Almadana-Pacheco, Virginia Cazorla, Maria Jesús Costa, Fabio Souza-Sokoloski, Caroline Çörtük, Mustafa Serra-Fortuny, Mireia Ortiz-de Saracho, Juan Lloret-Queraltó, Juan Antonio Rodriguez-Lázaro, Nuria Michel-de la Rosa, Francisco Javier Rodríguez-Hermosa, Juan Luis Saldaña-Pérez, Leonardo Akıncı, Elif Alonso, Javier Benítez-Buelga, Carlos Gómez-Mariano, Gema López-Campos, José Luis Martínez-Delgado, Beatriz |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Conferencia de Rectores de las Universidades Españolas Consejo Superior de Investigaciones Científicas (España) |
| dc.subject.none.fl_str_mv |
Alpha1 antitrypsin deficiency Diagnosis Mutations SERPINA1 |
| topic |
Alpha1 antitrypsin deficiency Diagnosis Mutations SERPINA1 |
| description |
[Background] Mutations in the SERPINA1 gene can result in alpha-1 antitrypsin deficiency (AATD), which may be associated with lung or liver injury. Although the S and Z alleles account for over 95% of cases of AATD, a wide variety of rare variants have been linked to deficiency and dysfunction, while other variants are associated with normal alpha-1 antitrypsin (AAT) levels and activity. Here, we present the identification and characterization of thirteen rare SERPINA1 variants discovered during the genetic diagnosis of AATD by the Progenika diagnostic network. |
| publishDate |
2026 |
| dc.date.none.fl_str_mv |
2026 2026 2026 |
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info:eu-repo/semantics/article Publisher's version info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/432047 https://api.elsevier.com/content/abstract/scopus_id/105030840148 |
| url |
http://hdl.handle.net/10261/432047 https://api.elsevier.com/content/abstract/scopus_id/105030840148 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1186/s12931-025-03486-1 https://doi.org/10.1186/s12931-025-03486-1 Sí |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Springer Nature BioMed Central |
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Springer Nature BioMed Central |
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Consejo Superior de Investigaciones Científicas (CSIC) |
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