Back to Journals » The Application of Clinical Genetics » Volume 14

Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

Authors Seixas S, Marques PI

Received 11 January 2021

Accepted for publication 24 February 2021

Published 22 March 2021 Volume 2021:14 Pages 173—194


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Martin H. Maurer

Susana Seixas,1,2 Patricia Isabel Marques1,2

1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; 2Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

Correspondence: Susana Seixas
i3S, Rua Alfredo Allen, 208, Porto, 4200-135, Portugal
Tel +351 220408806
Email [email protected]

Abstract: Alpha-1-Antitrypsin deficiency (AATD), caused by SERPINA1 mutations, is one of the most prevalent Mendelian disorders among individuals of European descend. However, this condition, which is characterized by reduced serum levels of alpha-1-antitrypsin (AAT) and associated with increased risks of pulmonary emphysema and liver disease in both children and adults, remains frequently underdiagnosed. AATD clinical manifestations are often correlated with two pathogenic variants, the Z allele (p.Glu342Lys) and the S allele (p.Glu264Val), which can be combined in severe ZZ or moderate SZ risk genotypes. Yet, screenings of AATD cases and large sequencing efforts carried out in both control and disease populations are disclosing outstanding numbers of rare SERPINA1 variants (> 500), including many pathogenic and other likely deleterious mutations. Generally speaking, pathogenic variants can be subdivided into either loss- or gain-of-function according to their pathophysiological effects. In AATD, the loss-of-function is correlated with an uncontrolled activity of elastase by its natural inhibitor, the AAT. This phenomenon can result from the absence of circulating AAT (null alleles), poor AAT secretion from hepatocytes (deficiency alleles) or even from a modified inhibitory activity (dysfunctional alleles). On the other hand, the gain-of-function is connected with the formation of AAT polymers and their switching on of cellular stress and inflammatory responses (deficiency alleles). Less frequently, the gain-of-function is related to a modified protease affinity (dysfunctional alleles). Here, we revisit SERPINA1 mutation spectrum, its origins and population history with a greater emphasis on variants fitting the aforementioned processes of AATD pathogenesis. Those were selected based on their clinical significance and wider geographic distribution. Moreover, we also provide some directions for future studies of AATD clinically heterogeneity and comprehensive diagnosis.

Keywords: SERPINA1 variants, Z allele, S allele, MMalton allele and QOurém allele

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]