Science and Research

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

Alpha-1 Antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum Alpha-1 Antitrypsin (AAT) due to mutations in the SERPINA1 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 S mutation, but producing null phenotype: QOVigo and QOAachen. The new alleles were identified by sequencing 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, while 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. 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 as 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 in order to improve the genetic diagnosis of the patients.

  • Matamala, N.
  • Gomez-Mariano, G.
  • Perez, J. A.
  • Baladron, B.
  • Torres-Duran, M.
  • Michel, F. J.
  • Saez, R.
  • Hernandez-Perez, J. M.
  • Belmonte, I.
  • Rodriguez-Frias, F.
  • Blanco, I.
  • Strnad, P.
  • Janciauskiene, S.
  • Martinez-Delgado, B.

Keywords

  • AAT polymerization
  • Alpha-1-antitrypsin
  • Genetic mutations
  • Pi*S allele
  • SERPINA1 gene
Publication details
DOI: 10.1165/rcmb.2020-0021OC
Journal: Am J Respir Cell Mol Biol
Work Type: Original
Location: BREATH
Disease Area: COPD
Partner / Member: MHH
Access-Number: 32515985
See publication on PubMed

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