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oai:repisalud.isciii.es:20.500.12105/172642024-11-29T10:50:55Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2052col_20.500.12105_16979col_20.500.12105_19616

00925njm 22002777a 4500 dc Matamala, Nerea author Gomez-Mariano, Gema Maria author Perez, Jose Antonio author Baladron-Jimenez, Beatriz Isabel author Torres-Durán, María author Michel, Francisco Javier author Saez, Raquel author Hernández-Pérez, Jose María author Belmonte, Irene author Rodriguez-Frias, Francisco author Blanco, Ignacio author Strnad, Pavel author Janciauskiene, Sabina author Martinez-Delgado, Beatriz author 2020-10 Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in the SERPINA1 (Serpin family A member 1) gene. The Pi*S (Glu264Val) is one of the most frequent deficient alleles of AATD, showing high incidence in the Iberian Peninsula. Herein, we describe two new alleles carrying an S mutation but producing a null phenotype: QOVigo and QOAachen. The new alleles were identified by sequencing the SERPINA1 gene in three patients who had lower AAT serum levels than expected for the initial genotype. These alleles are the result of combined mutations in cis in a PI*S allele. Sequencing detected the S mutation in cis with Tyr138Cys (S+Tyr138Cys) in two patients, whereas a third one had the S mutation in cis with Pro391Thr variant (S+Pro391Thr). When expressed in a cellular model, these variants caused strong AAT polymerization and very low AAT secretion to almost undetectable levels. The isoelectric focusing method for plasma AAT phenotyping did not show AAT protein encoded by the novel mutant alleles, behaving as null. We called these alleles PI*S-plus because the S variant was phased with another variant conferring more aggressive characteristics to the allele. The current data demonstrate that the clinical variability observed in AATD can be explained by additional genetic variation, such as dual cis-acting variants in the SERPINA1 gene. The possible existence of other unrevealed variants combined in the PI*S alleles should be considered to improve the genetic diagnosis of the patients. Am J Respir Cell Mol Biol. 2020 Oct;63(4):444-451. 10.1165/rcmb.2020-0021OC 1535-4989 American journal of respiratory cell and molecular biology 32515985 http://hdl.handle.net/20.500.12105/17264 Alpha-1 antitrypsin SERPINA 1 genetic mutations PI*S allele Polymerization New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency