New variants of alpha-1-antitrypsin

Alpha-1 antitrypsin deficiency (AATD) is characterized by reduced serum levels of the AAT protein and predisposes to liver and lung disease. The characterization at structural level of novel pathogenic SERPINA1 mutants coding for circulating AAT could provide novel insights into the mechanisms of AA...

Full description

Bibliographic Details
Authors: Gonzalez, Angel|||0000-0002-2284-8307, Belmonte, Irene|||0000-0002-8675-8343, Núñez, Alexa|||0000-0003-4067-0466, Farago, Georgina, Barrecheguren, Miriam|||0000-0002-6041-1499, Pons Delgado, Mònica|||0000-0002-0985-3320, Orriols, Gerard|||0000-0002-1138-5909, Gabriel-Medina, Pablo|||0000-0003-3079-6364, Rodríguez Frías, Francisco|||0000-0002-9128-7013, Miravitlles, Marc|||0000-0002-9850-9520, Esquinas, Cristina|||0000-0001-5568-257X
Format: article
Publication Date:2022
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:281753
Online Access:https://ddd.uab.cat/record/281753
https://dx.doi.org/urn:doi:10.1186/s12931-022-02271-8
Access Level:Open access
Keyword:Alpha-1 antitrypsin deficiency
SERPINA1 novel variants
Structural mapping
Molecular dynamic simulations
id ES_32f28cf233069f06759d709a76cd3f64
oai_identifier_str oai:ddd.uab.cat:281753
network_acronym_str ES
network_name_str España
repository_id_str
spelling New variants of alpha-1-antitrypsinstructural simulations and clinical expressionGonzalez, Angel|||0000-0002-2284-8307Belmonte, Irene|||0000-0002-8675-8343Núñez, Alexa|||0000-0003-4067-0466Farago, GeorginaBarrecheguren, Miriam|||0000-0002-6041-1499Pons Delgado, Mònica|||0000-0002-0985-3320Orriols, Gerard|||0000-0002-1138-5909Gabriel-Medina, Pablo|||0000-0003-3079-6364Rodríguez Frías, Francisco|||0000-0002-9128-7013Miravitlles, Marc|||0000-0002-9850-9520Esquinas, Cristina|||0000-0001-5568-257XAlpha-1 antitrypsin deficiencySERPINA1 novel variantsStructural mappingMolecular dynamic simulationsAlpha-1 antitrypsin deficiency (AATD) is characterized by reduced serum levels of the AAT protein and predisposes to liver and lung disease. The characterization at structural level of novel pathogenic SERPINA1 mutants coding for circulating AAT could provide novel insights into the mechanisms of AAT misfolding. The present study aimed to provide a practical framework for the identification and analysis of new AAT mutations, combining structural simulations and clinical data. We analysed a total of five mutations (four not previously described) in a total of six subjects presenting moderate to severe AATD: Gly95Alafs*18, Val210Glu, Asn247Ser, Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile. Clinical data, genotyping and phenotyping assays, structural mapping, and conformational characterization through molecular dynamic (MD) simulations were developed and combined. Newly discovered AAT missense variants were localized both on the interaction surface and the hydrophobic core of the protein. Distribution of mutations across the structure revealed Val210Glu at the solvent exposed s4C strand and close to the "Gate" region. Asn247Ser was located on the accessible surface, which is important for glycan attachment. On the other hand, Asp341His, Leu383Phe were mapped close to the "breach" and "shutter" regions. MD analysis revealed the reshaping of local interactions around the investigated substitutions that have varying effects on AAT conformational flexibility, hydrophobic packing, and electronic surface properties. The most severe structural changes were observed in the double- and triple-mutant (Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile) molecular models. The two carriers presented impaired lung function. The results characterize five variants, four of them previously unknown, of the SERPINA1 gene, which define new alleles contributing to the deficiency of AAT. Rare variants might be more frequent than expected, and therefore, in discordant cases, standardized screening of the S and Z alleles needs complementation with gene sequencing and structural approaches. The utility of computational modelling for providing supporting evidence of the pathogenicity of rare single nucleotide variations is discussed. The online version contains supplementary material available at 10.1186/s12931-022-02271-8. 22022-01-0120222022-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/281753https://dx.doi.org/urn:doi:10.1186/s12931-022-02271-8reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2817532026-06-06T12:50:31Z
dc.title.none.fl_str_mv New variants of alpha-1-antitrypsin
structural simulations and clinical expression
title New variants of alpha-1-antitrypsin
spellingShingle New variants of alpha-1-antitrypsin
Gonzalez, Angel|||0000-0002-2284-8307
Alpha-1 antitrypsin deficiency
SERPINA1 novel variants
Structural mapping
Molecular dynamic simulations
title_short New variants of alpha-1-antitrypsin
title_full New variants of alpha-1-antitrypsin
title_fullStr New variants of alpha-1-antitrypsin
title_full_unstemmed New variants of alpha-1-antitrypsin
title_sort New variants of alpha-1-antitrypsin
dc.creator.none.fl_str_mv Gonzalez, Angel|||0000-0002-2284-8307
Belmonte, Irene|||0000-0002-8675-8343
Núñez, Alexa|||0000-0003-4067-0466
Farago, Georgina
Barrecheguren, Miriam|||0000-0002-6041-1499
Pons Delgado, Mònica|||0000-0002-0985-3320
Orriols, Gerard|||0000-0002-1138-5909
Gabriel-Medina, Pablo|||0000-0003-3079-6364
Rodríguez Frías, Francisco|||0000-0002-9128-7013
Miravitlles, Marc|||0000-0002-9850-9520
Esquinas, Cristina|||0000-0001-5568-257X
author Gonzalez, Angel|||0000-0002-2284-8307
author_facet Gonzalez, Angel|||0000-0002-2284-8307
Belmonte, Irene|||0000-0002-8675-8343
Núñez, Alexa|||0000-0003-4067-0466
Farago, Georgina
Barrecheguren, Miriam|||0000-0002-6041-1499
Pons Delgado, Mònica|||0000-0002-0985-3320
Orriols, Gerard|||0000-0002-1138-5909
Gabriel-Medina, Pablo|||0000-0003-3079-6364
Rodríguez Frías, Francisco|||0000-0002-9128-7013
Miravitlles, Marc|||0000-0002-9850-9520
Esquinas, Cristina|||0000-0001-5568-257X
author_role author
author2 Belmonte, Irene|||0000-0002-8675-8343
Núñez, Alexa|||0000-0003-4067-0466
Farago, Georgina
Barrecheguren, Miriam|||0000-0002-6041-1499
Pons Delgado, Mònica|||0000-0002-0985-3320
Orriols, Gerard|||0000-0002-1138-5909
Gabriel-Medina, Pablo|||0000-0003-3079-6364
Rodríguez Frías, Francisco|||0000-0002-9128-7013
Miravitlles, Marc|||0000-0002-9850-9520
Esquinas, Cristina|||0000-0001-5568-257X
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alpha-1 antitrypsin deficiency
SERPINA1 novel variants
Structural mapping
Molecular dynamic simulations
topic Alpha-1 antitrypsin deficiency
SERPINA1 novel variants
Structural mapping
Molecular dynamic simulations
description Alpha-1 antitrypsin deficiency (AATD) is characterized by reduced serum levels of the AAT protein and predisposes to liver and lung disease. The characterization at structural level of novel pathogenic SERPINA1 mutants coding for circulating AAT could provide novel insights into the mechanisms of AAT misfolding. The present study aimed to provide a practical framework for the identification and analysis of new AAT mutations, combining structural simulations and clinical data. We analysed a total of five mutations (four not previously described) in a total of six subjects presenting moderate to severe AATD: Gly95Alafs*18, Val210Glu, Asn247Ser, Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile. Clinical data, genotyping and phenotyping assays, structural mapping, and conformational characterization through molecular dynamic (MD) simulations were developed and combined. Newly discovered AAT missense variants were localized both on the interaction surface and the hydrophobic core of the protein. Distribution of mutations across the structure revealed Val210Glu at the solvent exposed s4C strand and close to the "Gate" region. Asn247Ser was located on the accessible surface, which is important for glycan attachment. On the other hand, Asp341His, Leu383Phe were mapped close to the "breach" and "shutter" regions. MD analysis revealed the reshaping of local interactions around the investigated substitutions that have varying effects on AAT conformational flexibility, hydrophobic packing, and electronic surface properties. The most severe structural changes were observed in the double- and triple-mutant (Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile) molecular models. The two carriers presented impaired lung function. The results characterize five variants, four of them previously unknown, of the SERPINA1 gene, which define new alleles contributing to the deficiency of AAT. Rare variants might be more frequent than expected, and therefore, in discordant cases, standardized screening of the S and Z alleles needs complementation with gene sequencing and structural approaches. The utility of computational modelling for providing supporting evidence of the pathogenicity of rare single nucleotide variations is discussed. The online version contains supplementary material available at 10.1186/s12931-022-02271-8.
publishDate 2022
dc.date.none.fl_str_mv 2
2022-01-01
2022
2022-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
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 https://ddd.uab.cat/record/281753
https://dx.doi.org/urn:doi:10.1186/s12931-022-02271-8
url https://ddd.uab.cat/record/281753
https://dx.doi.org/urn:doi:10.1186/s12931-022-02271-8
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
https://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
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405707369971712
score 15.301603

Similar Items