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New variants of alpha-1-antitrypsin: structural simulations and clinical expression

BACKGROUND: 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 mech...

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Autores principales: Gonzalez, Angel, Belmonte, Irene, Nuñez, Alexa, Farago, Georgina, Barrecheguren, Miriam, Pons, Mònica, Orriols, Gerard, Gabriel-Medina, Pablo, Rodríguez-Frías, Francisco, Miravitlles, Marc, Esquinas, Cristina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9741788/
https://www.ncbi.nlm.nih.gov/pubmed/36496391
http://dx.doi.org/10.1186/s12931-022-02271-8
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author Gonzalez, Angel
Belmonte, Irene
Nuñez, Alexa
Farago, Georgina
Barrecheguren, Miriam
Pons, Mònica
Orriols, Gerard
Gabriel-Medina, Pablo
Rodríguez-Frías, Francisco
Miravitlles, Marc
Esquinas, Cristina
author_facet Gonzalez, Angel
Belmonte, Irene
Nuñez, Alexa
Farago, Georgina
Barrecheguren, Miriam
Pons, Mònica
Orriols, Gerard
Gabriel-Medina, Pablo
Rodríguez-Frías, Francisco
Miravitlles, Marc
Esquinas, Cristina
author_sort Gonzalez, Angel
collection PubMed
description BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-022-02271-8.
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spelling pubmed-97417882022-12-12 New variants of alpha-1-antitrypsin: structural simulations and clinical expression Gonzalez, Angel Belmonte, Irene Nuñez, Alexa Farago, Georgina Barrecheguren, Miriam Pons, Mònica Orriols, Gerard Gabriel-Medina, Pablo Rodríguez-Frías, Francisco Miravitlles, Marc Esquinas, Cristina Respir Res Research BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-022-02271-8. BioMed Central 2022-12-10 2022 /pmc/articles/PMC9741788/ /pubmed/36496391 http://dx.doi.org/10.1186/s12931-022-02271-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Gonzalez, Angel
Belmonte, Irene
Nuñez, Alexa
Farago, Georgina
Barrecheguren, Miriam
Pons, Mònica
Orriols, Gerard
Gabriel-Medina, Pablo
Rodríguez-Frías, Francisco
Miravitlles, Marc
Esquinas, Cristina
New variants of alpha-1-antitrypsin: structural simulations and clinical expression
title New variants of alpha-1-antitrypsin: structural simulations and clinical expression
title_full New variants of alpha-1-antitrypsin: structural simulations and clinical expression
title_fullStr New variants of alpha-1-antitrypsin: structural simulations and clinical expression
title_full_unstemmed New variants of alpha-1-antitrypsin: structural simulations and clinical expression
title_short New variants of alpha-1-antitrypsin: structural simulations and clinical expression
title_sort new variants of alpha-1-antitrypsin: structural simulations and clinical expression
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9741788/
https://www.ncbi.nlm.nih.gov/pubmed/36496391
http://dx.doi.org/10.1186/s12931-022-02271-8
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