Variants of SERPINA1 and the increasing complexity of testing for alpha-1 antitrypsin deficiency

Abstract

Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, which encodes the alpha-1 antitrypsin (AAT) protein. Currently, over 200 SERPINA1 variants have been identified, many of which cause the quantitative and/or qualitative changes in AAT responsible for AATD-associated lung and liver disease. The types of these pathogenic mutations are varied, often resulting in misfolding, or truncating of the AAT amino acid sequence, and improvements in sequencing technology are helping to identify known and novel genetic variants. However, due to the diversity and novelty of rare variants, the clinical significance of many is largely unknown. There is, therefore, a lack of guidance on how patients should be monitored and treated when the clinical significance of their variant combination is unclear or variable. Nevertheless, it is important that physicians understand the advantages and disadvantages of the different testing methodologies available to diagnose AATD. Owing to the autosomal inheritance of the genetic mutations responsible for AATD, genetic testing should be offered not only to patients at increased AATD risk (e.g. patients with chronic obstructive pulmonary disease), but also to relatives of those with an abnormal result. Genetic counseling may help patients and family members understand the possible outcomes of testing and the implications for the family. While stress/anxiety can arise from genetic diagnosis or confirmation of carrier status, there can be positive consequences to genetic testing, including improved lifestyle choices, directed medical care, and empowered family planning. As genetic testing technology grows and becomes more popular, testing without physician referral is becoming more prevalent, irrespective of the availability of genetic counseling. Therefore, the Alpha-1 Foundation offers genetic counseling, as well as other support and educational material, for patients with AATD, as well as their families and physicians, to help improve the understanding of potential benefits and consequences of genetic testing.

Structural characterization and conformational dynamics of alpha-1 antitrypsin pathogenic variants causing alpha-1-antitrypsin deficiency

“…Pathogenic variants in the SERPINA1 gene underlie alpha-1-antitrypsin deficiency (A1ATD), which causes reduced protein levels. Many pathogenic SERPINA1 variants associated with A1ATD have been reported in medical literature ( Foil, 2021 ). Biological characterization of each genetic variant is impractical owing to their high number and time-consuming laboratory methods.…”

“…The amino acid substitutions in A1AT may also alter the cellular function by forming polymer aggregates of the protein, causing liver and lung damage ( Duvoix et al, 2014 ). Many pathogenic alleles in SERPINA1 gene, also designated as protease inhibitor (PI), have already been described in A1ATD patients ( Foil, 2021 ). The misfolding and aggregation of this serpin family member is thermodynamically favorable since the protein’s native conformation is transient and built to be cleaved to reach stability ( Cho et al, 2005 ).…”

Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin

“…AATD is characterized by low levels of circulating alpha-1 antitrypsin (AAT), it is a risk factor for developing lung and/or liver diseases, as well as neutrophilic panniculitis or systemic vasculitis in some cases [1]. AATD is a monogenic condition caused by mutations in the SERPINA1 gene [2] encoding AAT, an acute phase glycoprotein and a major inhibitor of neutrophil elastase primarily synthetized in hepatocytes (by about 80%) and then released into the bloodstream, it also expressed to a lesser extent by monocytes and macrophages [3,4]. In addition, AAT is regarded as a multifunctional immunomodulatory protein that inhibits apoptosis and binds and neutralizes activities of cytokines and oxidants, among others [5,6].…”

“…The S allele (Glu206Val) originating from a point mutation in exon 3 and the Z allele (Glu342Lys) from a point mutation in exon 5 are the most common. In fact, about 96% of clinically recognized AATD cases carry the Z allele in homozygosity and only about 4-5% are heterozygous (Pi*SZ or Pi*MZ) or contain other rare alleles [2,8]. The Z allele is the most clinically relevant [7].…”

SerpinA1 levels in amyotrophic lateral sclerosis patients: An exploratory study

“…SerpinA1 is mainly expressed by hepatocytes, gastrointestinal epithelial cells, monocytes, and macrophages [11]. Although genetic mutations of the SERPINA1 gene were associated with increased risk of lung disease and/or liver disease [12], recent evidence highlights the potential protective role of SerpinA1 in the modulation of microglial-mediated inflammation, with implications for several neurodegenerative diseases [13,14]. In particular, SerpinA1 regulates proinflammatory cytokine release [15], binding to complement C3 [16] and modulating neutrophil functions [17], playing a decisive role during the acute phase of systemic inflammation.…”