PT  - JOURNAL ARTICLE
AU  - Nerea Matamala
AU  - Gema Gomez-Mariano
AU  - Jose Antonio Perez
AU  - Beatriz Baladron
AU  - María Torres-Durán
AU  - Francisco Javier Michel
AU  - Raquel Saez
AU  - Jose María Hernández-Pérez
AU  - Irene Belmonte
AU  - Francisco Rodriguez-Frias
AU  - Ignacio Blanco
AU  - Pavel Strnad
AU  - Sabina Janciauskiene
AU  - Beatriz Martinez-Delgado
TI  - PiS and PiS-plus alleles. The importance of phasing gene variants in Alpha-1 Antitrypsin Deficiency
AID  - 10.1183/13993003.congress-2020.2719
DP  - 2020 Sep 07
TA  - European Respiratory Journal
PG  - 2719
VI  - 56
IP  - suppl 64
4099  - http://erj.ersjournals.com/content/56/suppl_64/2719.short
4100  - http://erj.ersjournals.com/content/56/suppl_64/2719.full
SO  - Eur Respir J2020 Sep 07; 56
AB  - Alpha-1 Antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in SERPINA1 gene. Together, PiZ (Glu342Lys) and the PiS (Glu264Val) are the most frequent deficient alleles of AATD and reduce the protein level by 80% and 40% respectively. Genotyping of PiZ and PiS in AATD patients, is an important step in many diagnostic algorithms. However, there are deficient individuals with lower serum levels of AAT than expected for the initial genotype. In these cases sample must be further analyzed by sequencing of coding exons of SERPINA1 gene, and protein phenotyped by isoelectric focusing.In this study we describe two previously unknown missense variants, both confirmed to be in-cis configuration with the S mutation, producing a null phenotype. These novel variants were functionally characterized by expressing them in a cellular model. Data show that these variants modify the properties of the PiS allele resulting in higher intracellular retention and no extracellular secretion. Plasma sample analysis from patients carrying these combinations confirmed the null-phenotype behavior. These represent a novel type of AATD alleles that we named ‘PiS-plus’ alleles. Biochemically they have more pronounced pathogenic properties than typical deficient PiS alleles, while their clinical consequences need to be further explored. This finding highlights that genetic diagnosis of AATD should consider, in addition to identify gene variants, the phasing of these variants in order to establish a definitive diagnosis. The discovery of different PiS-plus alleles could help explaining the phenotypical variability observed among AATD patients.FootnotesCite this article as: European Respiratory Journal 2020; 56: Suppl. 64, 2719.This abstract was presented at the 2020 ERS International Congress, in session “Respiratory viruses in the "pre COVID-19" era”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).