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Title: Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency.
Authors: Matamala, Nerea
Lara, Beatriz
Gomez-Mariano, Gema
Martínez, Selene
Retana, Diana
Fernandez, Taiomara
Silvestre, Ramona Angeles
Belmonte, Irene
Rodriguez-Frias, Francisco
Vilar, Marçal
Sáez, Raquel
Iturbe, Igor
Castillo, Silvia
Molina-Molina, María
Texido, Anna
Tirado-Conde, Gema
Lopez-Campos, Jose Luis
Posada, Manuel
Blanco, Ignacio
Janciauskiene, Sabina
Martinez-Delgado, Beatriz
Keywords: SERPINA1 novel variants;alpha-1 antitrypsin deficiency;alpha-1 antitrypsin polymers;elastase
metadata.dc.subject.mesh: Adult
Gene Frequency
HEK293 Cells
Middle Aged
Mutant Proteins
Mutation, Missense
Protein Stability
alpha 1-Antitrypsin
alpha 1-Antitrypsin Deficiency
Issue Date: 2018
Abstract: 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.
metadata.dc.identifier.doi: 10.1165/rcmb.2017-0179OC
Appears in Collections:Producción 2020

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