{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:06:48Z","timestamp":1790946408140,"version":"4.1.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":25,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Respir Res"],"DOI":"10.1186\/s12931-025-03486-1","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T08:16:49Z","timestamp":1769761009000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency"],"prefix":"10.1186","volume":"27","author":[{"given":"Nerea","family":"Matamala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lourdes","family":"Osaba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estrella","family":"Drobnic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Gil-Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio J.","family":"Mart\u00edn-Galiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Almadana-Pacheco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jes\u00fas","family":"Cazorla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Souza-Sokoloski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"\u00c7\u00f6rt\u00fck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireia","family":"Serra-Fortuny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Ortiz-de Saracho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Antonio","family":"Lloret-Queralt\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Rodriguez-L\u00e1zaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Michel-de la Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Luis","family":"Rodr\u00edguez-Hermosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Salda\u00f1a-P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"Ak\u0131nc\u0131","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Alonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Ben\u00edtez-Buelga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gema","family":"G\u00f3mez-Mariano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Luis","family":"L\u00f3pez-Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Mart\u00ednez-Delgado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"3486_CR1","doi-asserted-by":"crossref","unstructured":"Stockley RA, Parr DG. Antitrypsin deficiency: still more to learn about the lung after 60\u2005years. ERJ Open Res 2024;10(4).","DOI":"10.1183\/23120541.00139-2024"},{"key":"3486_CR2","doi-asserted-by":"publisher","first-page":"173","DOI":"10.2147\/TACG.S257511","volume":"14","author":"S Seixas","year":"2021","unstructured":"Seixas S, Marques PI. Known mutations at the cause of alpha-1 antitrypsin deficiency an updated overview of serpina1 variation spectrum. Appl Clin Genet. 2021;14:173\u201394.","journal-title":"Appl Clin Genet"},{"issue":"7","key":"3486_CR3","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.arbres.2023.03.016","volume":"59","author":"I Blanco","year":"2023","unstructured":"Blanco I, Diego I, Casta\u00f1\u00f3n C, Bueno P, Miravitlles M. Estimated worldwide prevalence of the pi*zz alpha-1 antitrypsin genotype in subjects with chronic obstructive pulmonary disease. Arch Bronconeumol. 2023;59(7):427\u201334.","journal-title":"Arch Bronconeumol"},{"issue":"9","key":"3486_CR4","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.arbres.2024.05.031","volume":"60","author":"G Scioscia","year":"2024","unstructured":"Scioscia G, Santacroce R, Tondo P, Hoxhallari A, Soccio P, Giuffreda E, D\u2019Ambrosio MF, Leccese A, Paladini L, Natale MP, et al. A report on a targeted screening population for alpha-1-antitrypsin deficiency (aatd) in central-southern Italy. Arch Bronconeumol. 2024;60(9):595\u20137.","journal-title":"Arch Bronconeumol"},{"issue":"1","key":"3486_CR5","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1186\/s13023-024-03069-1","volume":"19","author":"I Ferrarotti","year":"2024","unstructured":"Ferrarotti I, Wencker M, Chorostowska-Wynimko J. Rare variants in alpha 1 antitrypsin deficiency: A systematic literature review. Orphanet J Rare Dis. 2024;19(1):82.","journal-title":"Orphanet J Rare Dis"},{"issue":"7","key":"3486_CR6","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.arbres.2023.02.016","volume":"59","author":"JM Hern\u00e1ndez-P\u00e9rez","year":"2023","unstructured":"Hern\u00e1ndez-P\u00e9rez JM, Mart\u00edn-Gonz\u00e1lez E, Gonz\u00e1lez-Carracedo MA. Alpha-1 antitrypsin deficiency and serpina1 variants could play a role in asthma exacerbations. Arch Bronconeumol. 2023;59(7):416\u20137.","journal-title":"Arch Bronconeumol"},{"issue":"1","key":"3486_CR7","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s40246-023-00497-1","volume":"17","author":"JL Lopez-Campos","year":"2023","unstructured":"Lopez-Campos JL, Rapun N, Czischke K, Jardim JR, Acquier MF, Munive AA, G\u00fcnen H, Drobnic E, Miravitlles M, Osaba L. Distribution of alpha1 antitrypsin rare alleles in six countries: results from the progenika diagnostic network. Hum Genomics. 2023;17(1):48.","journal-title":"Hum Genomics"},{"issue":"1","key":"3486_CR8","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1186\/s12931-022-02074-x","volume":"23","author":"JL Lopez-Campos","year":"2022","unstructured":"Lopez-Campos JL, Osaba L, Czischke K, Jardim JR, Fernandez Acquier M, Ali A, G\u00fcnen H, Rapun N, Drobnic E, Miravitlles M. Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: A multinational cross-sectional analysis. Respir Res. 2022;23(1):152.","journal-title":"Respir Res"},{"issue":"W1","key":"3486_CR9","doi-asserted-by":"publisher","first-page":"W296","DOI":"10.1093\/nar\/gky427","volume":"46","author":"A Waterhouse","year":"2018","unstructured":"Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer TAP, Rempfer C, Bordoli L, et al. Swiss-model: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46(W1):W296\u2013303.","journal-title":"Nucleic Acids Res"},{"issue":"Pt 12","key":"3486_CR10","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1107\/S1744309111040267","volume":"67","author":"AO Patschull","year":"2011","unstructured":"Patschull AO, Segu L, Nyon MP, Lomas DA, Nobeli I, Barrett TE, Gooptu B. Therapeutic target-site variability in \u03b11-antitrypsin characterized at high resolution. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011;67(Pt 12):1492\u20137.","journal-title":"Acta Crystallogr Sect F Struct Biol Cryst Commun"},{"issue":"6","key":"3486_CR11","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1165\/rcmb.2017-0179OC","volume":"58","author":"N Matamala","year":"2018","unstructured":"Matamala N, Lara B, Gomez-Mariano G, Mart\u00ednez S, Retana D, Fernandez T, Silvestre RA, Belmonte I, Rodriguez-Frias F, Vilar M, et al. Characterization of novel missense variants of serpina1 gene causing alpha-1 antitrypsin deficiency. Am J Respir Cell Mol Biol. 2018;58(6):706\u201316.","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"5","key":"3486_CR12","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17(5):405\u201324.","journal-title":"Genet Med"},{"issue":"1","key":"3486_CR13","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1186\/s13023-018-0897-0","volume":"13","author":"C Renoux","year":"2018","unstructured":"Renoux C, Odou MF, Tosato G, Teoli J, Abbou N, Lombard C, Zerimech F, Porchet N, Chapuis Cellier C, Balduyck M, et al. Description of 22 new alpha-1 antitrypsin genetic variants. Orphanet J Rare Dis. 2018;13(1):161.","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"3486_CR14","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1186\/s12931-022-02271-8","volume":"23","author":"A Gonzalez","year":"2022","unstructured":"Gonzalez A, Belmonte I, Nu\u00f1ez A, Farago G, Barrecheguren M, Pons M, Orriols G, Gabriel-Medina P, Rodr\u00edguez-Fr\u00edas F, Miravitlles M, et al. New variants of alpha-1-antitrypsin: structural simulations and clinical expression. Respir Res. 2022;23(1):339.","journal-title":"Respir Res"},{"issue":"1","key":"3486_CR15","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.arbr.2020.04.010","volume":"57","author":"JL Lopez-Campos","year":"2021","unstructured":"Lopez-Campos JL, Casas-Maldonado F, Torres-Duran M, Medina-Gonz\u00e1lvez A, Rodriguez-Fidalgo ML, Carrascosa I, Calle M, Osaba L, Rapun N, Drobnic E, et al. Results of a diagnostic procedure based on multiplex technology on dried blood spots and buccal swabs for subjects with suspected alpha1 antitrypsin deficiency. Arch Bronconeumol (Engl Ed). 2021;57(1):42\u201350.","journal-title":"Arch Bronconeumol (Engl Ed)"},{"key":"3486_CR16","doi-asserted-by":"publisher","first-page":"2836389","DOI":"10.1155\/2018\/2836389","volume":"2018","author":"KE Foil","year":"2018","unstructured":"Foil KE, Blanton MG, Sanders C, Kim J, Al Ashry HS, Kumbhare S, Strange C. Sequencing alpha-1 Mz individuals shows frequent biallelic mutations. Pulm Med. 2018;2018:2836389.","journal-title":"Pulm Med"},{"issue":"10","key":"3486_CR17","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/nrg907","volume":"3","author":"DA Lomas","year":"2002","unstructured":"Lomas DA, Carrell RW. Serpinopathies and the conformational dementias. Nat Rev Genet. 2002;3(10):759\u201368.","journal-title":"Nat Rev Genet"},{"key":"3486_CR18","doi-asserted-by":"publisher","first-page":"985892","DOI":"10.3389\/fped.2022.985892","volume":"10","author":"JM Hern\u00e1ndez-P\u00e9rez","year":"2022","unstructured":"Hern\u00e1ndez-P\u00e9rez JM, Gonz\u00e1lez Carracedo MA, Garc\u00eda AC, P\u00e9rez JAP. Molecular characterization of Pi (*) s (hangzhou), a serpina1 allele from continental China encoding a defective alpha-1-antitrypsin. Front Pediatr. 2022;10:985892.","journal-title":"Front Pediatr"},{"key":"3486_CR19","doi-asserted-by":"crossref","unstructured":"Ronzoni R, Ferrarotti I, D\u2019Acunto E, Balderacchi AM, Ottaviani S, Lomas DA, Irving JA, Miranda E, Fra A. The importance of n186 in the alpha-1-antitrypsin shutter region is revealed by the novel Bologna deficiency variant. Int J Mol Sci 2021;22(11).","DOI":"10.3390\/ijms22115668"},{"issue":"3","key":"3486_CR20","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1165\/rcmb.2022-0470OC","volume":"69","author":"S Ottaviani","year":"2023","unstructured":"Ottaviani S, Bartoli G, Carroll TP, Gangemi F, Balderacchi AM, Barzon V, Corino A, Piloni D, McElvaney NG, Corsico AG, et al. Comprehensive clinical diagnostic pipelines reveal new variants in alpha-1 antitrypsin deficiency. Am J Respir Cell Mol Biol. 2023;69(3):355\u201366.","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"9","key":"3486_CR21","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1002\/humu.23562","volume":"39","author":"E Giacopuzzi","year":"2018","unstructured":"Giacopuzzi E, Laffranchi M, Berardelli R, Ravasio V, Ferrarotti I, Gooptu B, Borsani G, Fra A. Real-world clinical applicability of pathogenicity predictors assessed on serpina1 mutations in alpha-1-antitrypsin deficiency. Hum Mutat. 2018;39(9):1203\u201313.","journal-title":"Hum Mutat"},{"issue":"1","key":"3486_CR22","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/s12881-019-0852-5","volume":"20","author":"F Kueppers","year":"2019","unstructured":"Kueppers F, Andrake MD, Xu Q, Dunbrack RL Jr., Kim J, Sanders CL. Protein modeling to assess the pathogenicity of rare variants of serpina1 in patients suspected of having alpha 1 antitrypsin deficiency. BMC Med Genet. 2019;20(1):125.","journal-title":"BMC Med Genet"},{"key":"3486_CR23","doi-asserted-by":"publisher","first-page":"1051511","DOI":"10.3389\/fmolb.2022.1051511","volume":"9","author":"NA Shaik","year":"2022","unstructured":"Shaik NA, Saud Al-Saud NB, Abdulhamid Aljuhani T, Jamil K, Alnuman H, Aljeaid D, Sultana N, El-Harouni AA, Awan ZA, Elango R, et al. Structural characterization and conformational dynamics of alpha-1 antitrypsin pathogenic variants causing alpha-1-antitrypsin deficiency. Front Mol Biosci. 2022;9:1051511.","journal-title":"Front Mol Biosci"},{"issue":"3","key":"3486_CR24","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/sj.ejhg.5200304","volume":"7","author":"W Poller","year":"1999","unstructured":"Poller W, Merklein F, Schneider-Rasp S, Haack A, Fechner H, Wang H, Anagnostopoulos I, Weidinger S. Molecular characterisation of the defective alpha 1-antitrypsin alleles Pi Mwurzburg (pro369ser), Mheerlen (pro369leu), and q0lisbon (thr68ile). Eur J Hum Genet. 1999;7(3):321\u201331.","journal-title":"Eur J Hum Genet"},{"issue":"1","key":"3486_CR25","first-page":"7","volume":"10","author":"GS Wiesemann","year":"2023","unstructured":"Wiesemann GS, Oshins RA, Flagg TO, Brantly ML. Novel serpina1 alleles identified through a large alpha-1 antitrypsin deficiency screening program and review of known variants. Chronic Obstr Pulm Dis. 2023;10(1):7\u201321.","journal-title":"Chronic Obstr Pulm Dis"},{"issue":"40","key":"3486_CR26","doi-asserted-by":"publisher","first-page":"17146","DOI":"10.1073\/pnas.1004785107","volume":"107","author":"UI Ekeowa","year":"2010","unstructured":"Ekeowa UI, Freeke J, Miranda E, Gooptu B, Bush MF, P\u00e9rez J, Teckman J, Robinson CV, Lomas DA. Defining the mechanism of polymerization in the serpinopathies. Proc Natl Acad Sci U S A. 2010;107(40):17146\u201351.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"3486_CR27","doi-asserted-by":"crossref","unstructured":"Haq I, Irving JA, Faull SV, Dickens JA, Ord\u00f3\u00f1ez A, Belorgey D, Gooptu B, Lomas DA. Reactive centre loop mutants of \u03b1-1-antitrypsin reveal position-specific effects on intermediate formation along the polymerization pathway. Biosci Rep 2013;33(3).","DOI":"10.1042\/BSR20130038"},{"issue":"1","key":"3486_CR28","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1165\/rcmb.2015-0154OC","volume":"54","author":"I Haq","year":"2016","unstructured":"Haq I, Irving JA, Saleh AD, Dron L, Regan-Mochrie GL, Motamedi-Shad N, Hurst JR, Gooptu B, Lomas DA. Deficiency mutations of alpha-1 antitrypsin. Effects on folding, function, and polymerization. Am J Respir Cell Mol Biol. 2016;54(1):71\u201380.","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"1","key":"3486_CR29","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s00018-023-05059-1","volume":"81","author":"A Denardo","year":"2023","unstructured":"Denardo A, Ben Khlifa E, Bignotti M, Giuliani R, D\u2019Acunto E, Miranda E, Irving JA, Fra A. Probing of the reactive center loop region of alpha-1-antitrypsin by mutagenesis predicts new type-2 dysfunctional variants. Cell Mol Life Sci. 2023;81(1):6.","journal-title":"Cell Mol Life Sci"}],"container-title":["Respiratory Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12931-025-03486-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12931-025-03486-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12931-025-03486-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T23:04:41Z","timestamp":1771974281000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12931-025-03486-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,30]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3486"],"URL":"https:\/\/doi.org\/10.1186\/s12931-025-03486-1","relation":{},"ISSN":["1465-993X"],"issn-type":[{"value":"1465-993X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,30]]},"assertion":[{"value":"12 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 December 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study reports the results of a diagnostic procedure that is approved for use in all the participating countries and, therefore, constitutes standard clinical practice. Consequently, since it is not an experimental procedure, approval by an ethics committee was not considered necessary. All patients included signed a written informed consent form.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Signed informed consent was obtained from patients.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"LO is full-time employee of Progenika, ED is full-time employee of Grifols.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"95"}}