New cis -Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency

American Journal of Respiratory Cell and Molecular Biology, vol. 63, pp. 444–451

Abstract

Abstract 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.

Authors 13

1. Nerea Matamala

   Instituto de Salud Carlos III · Instituto de Investigación de Enfermedades Raras

   Affiliation as printed

   Molecular Genetics Unit, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain

2. Gema Gómez‐Mariano

   Instituto de Salud Carlos III · Instituto de Investigación de Enfermedades Raras

   Affiliation as printed

   Molecular Genetics Unit, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain

3. José Antonio Pérez Pérez

   Universidad de La Laguna

   Affiliation as printed

   Área de Genética, Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, Tenerife, Spain

4. Beatriz Baladrón

   Instituto de Salud Carlos III · Instituto de Investigación de Enfermedades Raras

   Affiliation as printed

   Molecular Genetics Unit, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain

5. María Torres‐Durán

   Estructura Organizativa de Xestión Integrada de Vigo

   Affiliation as printed

   Servicio de Neumología, Hospital Álvaro Cunqueiro, Estructura Organizativa de Xestión Integrada Vigo, Pneumovigo I + i, Instituto de Investigación Sanitaria Galicia Sur, Vigo, Spain

6. Francisco Javier Michel
   Affiliation as printed

   Servicio de Neumología, and

7. José María Hernández Pérez
   Affiliation as printed

   Servicio de Neumología, Hospital General de la Palma, Canarias, Spain

8. Irene Belmonte

   Vall d'Hebron Hospital Universitari

   Affiliation as printed

   Biochemistry Department, Hospital Vall d’Hebron, Barcelona, Spain

9. Francisco Rodríguez‐Frias

   Vall d'Hebron Hospital Universitari

   Affiliation as printed

   Biochemistry Department, Hospital Vall d’Hebron, Barcelona, Spain

10. Ignacio Blanco

    Sociedad Española de Neumología y Cirugía Torácica

    Affiliation as printed

    Registro Español de Pacientes con Déficit de Alfa-1 Antitripsina, Fundación Española, de Pulmón, Respira, Sociedad Española de Neumología y Cirugía Torácica, Barcelona, Spain

11. Pavel Strnad Aachen Department of Internal Medicine III

    Universitätsklinikum Aachen

    Affiliation as printed

    Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany

12. Sabina M Janciauskiene

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Department of Respiratory Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, Hannover Medical School, Hannover, Germany; and

13. Beatriz Martínez–Delgado corresponding

    Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases · Instituto de Investigación de Enfermedades Raras

    Affiliation as printed

    Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain

    Molecular Genetics Unit, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain