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oai:repisalud.isciii.es:20.500.12105/106002025-06-17T08:50:00Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2052col_20.500.12105_16958col_20.500.12105_16962col_20.500.12105_19616

00925njm 22002777a 4500 dc Lara, Beatriz author Fernandez, Taiomara author Silvestre, Ramona Angeles author Belmonte, Irene author Rodriguez-Frias, Francisco author Vilar, Marçal author Sáez, Raquel author Iturbe, Igor author Castillo, Silvia author Molina-Molina, María author Texido, Anna author Tirado-Conde, Gema author Lopez-Campos, Jose Luis author Blanco, Ignacio author Janciauskiene, Sabina author Matamala, Nerea author Gomez-Mariano, Gema Maria author Martinez Rodríguez, Selene author Retana, Diana author Posada De la Paz, Manuel author Martinez-Delgado, Beatriz author 2018 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. Am J Respir Cell Mol Biol . 2018 Jun;58(6):706-716. 10.1165/rcmb.2017-0179OC 1535-4989 American journal of respiratory cell and molecular biology 29232161 http://hdl.handle.net/20.500.12105/10600 Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency