Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Mar 22:14:173-194.
doi: 10.2147/TACG.S257511. eCollection 2021.

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

Susana Seixas  1   2 , Patricia Isabel Marques  1   2
Affiliations
Review

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

Susana Seixas et al. Appl Clin Genet. .

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: MMalton allele and QOurém allele; S allele; SERPINA1 variants; Z allele.

PubMed Disclaimer

Conflict of interest statement

The authors have no competing interests to declare.

Figures

Figure 1
Figure 1
(A) SERPINA1 expression across different tissues. The graph was built in GTEx portal (https://gtexportal.org/home/) using the RNAseq data from multiple individuals generated by the Genotype-Tissue Expression (GTEx) project. (B) Three-dimensional structure of an active AAT molecule (PDB code: 1QLP). The breach, shutter and gate domains are highlighted by dark blue circles. The reactive center loop (RCL) and Met-Ser bond (P1-P1ʹ) therein are indicated. (C) Three-dimensional structure of an AAT molecule bond to trypsin in a protease-inhibitor complex (PDB code: 1EXZ). The inserted β-strand of the RCL and the Met358 and Ser359 residues from the cleaved P1-P1ʹ are indicated. α-helixes are shown in light blue, β-strands in red and loops in magenta. The three-dimensional images were generated using PyMOL.
Figure 2
Figure 2
AAT phenotypes as obtained by IEF in polyacrylamide gels after Coomassie blue staining (left side) and schematic representation of major diagnostic bands of AAT alleles.
Figure 3
Figure 3
Three-dimensional structure of an active AAT molecule (PDB code: 1QLP) displaying the mutated residues in selected pathogenic AAT alleles. Amino acids affected in variants with increased polymerization susceptibility are shown in red, in dysfunctional alleles are highlighted in blue, in null alleles are displayed in green and combining polymerogenic and null alleles are presented in orange. The three-dimensional images were generated using PyMOL.
Figure 4
Figure 4
(A) SERPINA1 cis-quantitative trait loci (QTL) view in Genotype-Tissue Expression (GTEx) Locus Browser (https://gtexportal.org/home/). The top section shows the genomic region 1Mb up- and downstream of SERPINA1. In the middle, expression QTLs (eQTL) and splicing QTLs (sQTL) of SERPINA1 are portrayed as bar charts in lung and whole blood with the –log10(p-value) represented in the y-axis. The liver tissue was not available for QTLs analysis. The variant with the most significant p-value – rs2854254 – is highlighted by a red star symbol. The last row shows the functional annotation of the variants according to Ensembl’s Variant Predictor (VEP), Loss-Of-Function Transcript Effect (LOFTEE) and Ensembl Regulatory Build. At the bottom, the plot depicts the pairwise linkage disequilibrium (LD) values (R2) of the QTL variants. TSS, transcription start site; TES, transcription end site. (B) Violin plots of allele-specific cis-sQTL effects of rs2854254 genotypes on SERPINA1 in human lung and whole blood (GTEx database – GTEx Analysis Release v8).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lopes AP, Mineiro MA, Costa F, et al. Portuguese consensus document for the management of alpha-1-antitrypsin deficiency. Pulmonology. 2018;24(Suppl 1):1–21. doi:10.1016/j.pulmoe.2018.09.004 - DOI - PubMed
    1. Silva D, Oliveira MJ, Guimarães M, Lima R, Gomes S, Seixas S. Alpha-1-antitrypsin (SERPINA1) mutation spectrum: three novel variants and haplotype characterization of rare deficiency alleles identified in Portugal. Respir Med. 2016;116:8–18. doi:10.1016/j.rmed.2016.05.002 - DOI - PubMed
    1. Stein PE, Carrell RW. What do dysfunctional serpins tell us about molecular mobility and disease? Nat Struct Biol. 1995;2(2):96–113. doi:10.1038/nsb0295-96 - DOI - PubMed
    1. Janciauskiene SM, Bals R, Koczulla R, Vogelmeier C, Kohnlein T, Welte T. The discovery of alpha1-antitrypsin and its role in health and disease. Respir Med. 2011;105(8):1129–1139. doi:10.1016/j.rmed.2011.02.002 - DOI - PubMed
    1. ATS/ERS. American thoracic society/European respiratory society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818–900. doi:10.1164/rccm.168.7.818. - DOI - PubMed