RT Journal Article
T1 Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency.
A1 Matamala, Nerea
A1 Lara, Beatriz
A1 Gomez-Mariano, Gema
A1 Martinez, Selene
A1 Retana, Diana
A1 Fernandez, Taiomara
A1 Silvestre, Ramona Angeles
A1 Belmonte, Irene
A1 Rodriguez-Frias, Francisco
A1 Vilar, Marçal
A1 Saez, Raquel
A1 Iturbe, Igor
A1 Castillo, Silvia
A1 Molina-Molina, Maria
A1 Texido, Anna
A1 Tirado-Conde, Gema
A1 Lopez-Campos, Jose Luis
A1 Posada, Manuel
A1 Blanco, Ignacio
A1 Janciauskiene, Sabina
A1 Martinez-Delgado, Beatriz
K1 SERPINA1 novel variants
K1 alpha-1 antitrypsin deficiency
K1 alpha-1 antitrypsin polymers
K1 elastase
AB 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.
PB American Thoracic Society
YR 2018
FD 2018
LK http://hdl.handle.net/10668/11897
UL http://hdl.handle.net/10668/11897
LA en
NO Matamala N, Lara B, Gomez-Mariano G, Martínez S, Retana D, Fernandez T, et al. Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency. Am J Respir Cell Mol Biol. 2018 Jun;58(6):706-716.
DS RISalud
RD Apr 9, 2025