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PiS and PiS-plus alleles. The importance of phasing gene variants in Alpha-1 Antitrypsin Deficiency

Nerea Matamala, Gema Gomez-Mariano, Jose Antonio Perez, Beatriz Baladron, María Torres-Durán, Francisco Javier Michel, Raquel Saez, Jose María Hernández-Pérez, Irene Belmonte, Francisco Rodriguez-Frias, Ignacio Blanco, Pavel Strnad, Sabina Janciauskiene, Beatriz Martinez-Delgado
European Respiratory Journal 2020 56: 2719; DOI: 10.1183/13993003.congress-2020.2719
Nerea Matamala
1Molecular Genetics Unit, Instituto de Investigación de Enfermedades Raras (IIER). Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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  • For correspondence: neremat@hotmail.com
Gema Gomez-Mariano
1Molecular Genetics Unit, Instituto de Investigación de Enfermedades Raras (IIER). Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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Jose Antonio Perez
2Área de Genética. Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, Canarias, Spain
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Beatriz Baladron
1Molecular Genetics Unit, Instituto de Investigación de Enfermedades Raras (IIER). Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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María Torres-Durán
3Servicio de Neumología. Hospital Álvaro Cunqueiro. EOXI Vigo. Pneumovigo I+i. IIS Galicia Sur, Vigo, Spain
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Francisco Javier Michel
4Servicio de Neumología. Hospital Universitario Donostia, Donostia, Spain
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Raquel Saez
5Genetics and Inmunology. Hospital Universitario Donostia, Donostia, Spain
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Jose María Hernández-Pérez
6Servicio de Neumología. Hospital General de la Palma, Canarias, Spain
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Irene Belmonte
7Biochemistry Department. Hospital Vall d’Hebron, Barcelona, Spain
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Francisco Rodriguez-Frias
7Biochemistry Department. Hospital Vall d’Hebron, Barcelona, Spain
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Ignacio Blanco
8Registro Español de pacientes con déficit de alfa-1 antitripsina (REDAAT). Fundación Española, Barcelona, Spain
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Pavel Strnad
9Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany
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Sabina Janciauskiene
10Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
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Beatriz Martinez-Delgado
1Molecular Genetics Unit, Instituto de Investigación de Enfermedades Raras (IIER). Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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Abstract

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.

  • COPD - diagnosis
  • Mutations
  • Genetics

Footnotes

Cite 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).

  • Copyright ©the authors 2020
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PiS and PiS-plus alleles. The importance of phasing gene variants in Alpha-1 Antitrypsin Deficiency
Nerea Matamala, Gema Gomez-Mariano, Jose Antonio Perez, Beatriz Baladron, María Torres-Durán, Francisco Javier Michel, Raquel Saez, Jose María Hernández-Pérez, Irene Belmonte, Francisco Rodriguez-Frias, Ignacio Blanco, Pavel Strnad, Sabina Janciauskiene, Beatriz Martinez-Delgado
European Respiratory Journal Sep 2020, 56 (suppl 64) 2719; DOI: 10.1183/13993003.congress-2020.2719

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PiS and PiS-plus alleles. The importance of phasing gene variants in Alpha-1 Antitrypsin Deficiency
Nerea Matamala, Gema Gomez-Mariano, Jose Antonio Perez, Beatriz Baladron, María Torres-Durán, Francisco Javier Michel, Raquel Saez, Jose María Hernández-Pérez, Irene Belmonte, Francisco Rodriguez-Frias, Ignacio Blanco, Pavel Strnad, Sabina Janciauskiene, Beatriz Martinez-Delgado
European Respiratory Journal Sep 2020, 56 (suppl 64) 2719; DOI: 10.1183/13993003.congress-2020.2719
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