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Am J Respir Cell Mol Biol. 2018 Jun;58(6):706-716. doi: 10.1165/rcmb.2017-0179OC.

Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency.

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1 Molecular Genetics Unit, Instituto de Investigación de Enfermedades Raras (IIER).
2 Respiratory Medicine Department, Coventry University Hospital, Coventry, United Kingdom.
3 Biochemistry Unit, Hospital Puerta de Hierro, Madrid, Spain.
4 Biochemistry Department, Hospital Vall d'Hebron, Barcelona, Spain.
5 Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientificas (CSIC), Valencia, Spain.
6 Immunology and Genetics, Hospital Donosti, San Sebastián, Spain.
7 Pneumology, Hospital de Zumárraga, Gipuzkoa, Spain.
8 Pediatrics, Hospital Clínico de Valencia, Valencia, Spain.
9 Pulmonary Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Hospital de Llobregat, Barcelona, Spain.
10 Pneumology, Hospital Universitari Sant Joan de Reus, Reus (Tarragona), Spain.
11 Complejo Hospitalario Universitario Granada, Parque Tecnológico de las Ciencias de la Salud, Granada, Spain.
13 Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), and.
12 Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/Universidad de Sevilla, Sevilla, Spain.
14 Consorcio Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
15 Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency (REDAAT), Spanish Society of Pneumology (SEPAR), Fundación Española de Pulmón (RESPIRA), Barcelona, Spain.
16 Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; and.
17 Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany.


The SERPINA1 gene is highly polymorphic, with more than 100 variants described in databases. SERPINA1 encodes the alpha-1 antitrypsin (AAT) protein, and severe deficiency of AAT is a major contributor to pulmonary emphysema and liver diseases. In Spanish patients with AAT deficiency, we identified seven new variants of the SERPINA1 gene involving amino acid substitutions in different exons: PiSDonosti (S+Ser14Phe), PiTijarafe (Ile50Asn), PiSevilla (Ala58Asp), PiCadiz (Glu151Lys), PiTarragona (Phe227Cys), PiPuerto Real (Thr249Ala), and PiValencia (Lys328Glu). We examined the characteristics of these variants and the putative association with the disease. Mutant proteins were overexpressed in HEK293T cells, and AAT expression, polymerization, degradation, and secretion, as well as antielastase activity, were analyzed by periodic acid-Schiff staining, Western blotting, pulse-chase, and elastase inhibition assays. When overexpressed, S+S14F, I50N, A58D, F227C, and T249A variants formed intracellular polymers and did not secrete AAT protein. Both the E151K and K328E variants secreted AAT protein and did not form polymers, although K328E showed intracellular retention and reduced antielastase activity. We conclude that deficient variants may be more frequent than previously thought and that their discovery is possible only by the complete sequencing of the gene and subsequent functional characterization. Better knowledge of SERPINA1 variants would improve diagnosis and management of individuals with AAT deficiency.


SERPINA1 novel variants; alpha-1 antitrypsin deficiency; alpha-1 antitrypsin polymers; elastase


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