2024-03-29T01:01:16Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/106002023-03-06T12:59:45Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2102com_20.500.12105_2052col_20.500.12105_16962col_20.500.12105_16958col_20.500.12105_2103
Repisalud
author
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
funder
Instituto de Salud Carlos III
2020-06-26T17:24:37Z
2020-06-26T17:24:37Z
2018
Am J Respir Cell Mol Biol . 2018 Jun;58(6):706-716.
http://hdl.handle.net/20.500.12105/10600
29232161
10.1165/rcmb.2017-0179OC
1535-4989
American journal of respiratory cell and molecular biology
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.
eng
Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency.
journal article
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URL
https://repisalud.isciii.es/bitstream/20.500.12105/10600/1/CharacterizationOfNovelMissense_2018.pdf
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CharacterizationOfNovelMissense_2018.pdf
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https://repisalud.isciii.es/bitstream/20.500.12105/10600/6/CharacterizationOfNovelMissense_2018.pdf.txt
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CharacterizationOfNovelMissense_2018.pdf.txt