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

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.

Estimated Prevalence and Number of PiMZ Genotypes of Alpha-1 Antitrypsin in Seventy-Four Countries Worldwide

“…Alpha-1 antitrypsin deficiency (AATD) is a genetic condition, transmitted by autosomal codominant inheritance, caused by mutations of the SERPIN A1 gene, of which more than 120 variants have been identified, and about 40% of them can cause AATD. 2 The vast majority of SERPIN A1 genotypes result from combinations between the normal protease inhibitor (Pi) M allele and the most frequent deficiency alleles PiS and PiZ, namely PiMM, PiMS, PiSS, PiMZ, PiSZ and PiZZ, which roughly express 100%, 80%, 60%, 55%, 40% and 15% of serum AAT, respectively. 3 , 4…”

“…1 Alpha-1 antitrypsin deficiency (AATD) is a genetic condition, transmitted by autosomal codominant inheritance, caused by mutations of the SERPINA1 gene, of which more than 120 variants have been identified, and about 40% of them can cause AATD. 2 The vast majority of SERPINA1 genotypes result from combinations between the normal protease inhibitor (Pi) M allele and the most frequent deficiency alleles PiS and PiZ, namely PiMM, PiMS, PiSS, PiMZ, PiSZ and PiZZ, which roughly express 100%, 80%, 60%, 55%, 40% and 15% of serum AAT, respectively. 3,4 The Z allelic variant (Glu342Lys) is characterized by the production of a defective protein with marked conformational changes causing the formation of AAT-Z polymers that are retained within hepatocytes without being secreted into the blood, and a loss of their inhibitory capacity of 80-90%.…”

“…5 In clinical practice, severe AATD is associated with PiZZ genotypes in more than 95% of the cases, and it can manifest clinically as infantile cholestasis (~11%), liver fibrosis or cirrhosis at all ages of life (~30%), chronic obstructive pulmonary disease (COPD) (~60-80%), and much less frequently as neutrophilic panniculitis, granulomatosis with polyangiitis and hepatocarcinomas, although between a third or a half of ZZ subjects not exposed to risk factors (especially tobacco smoke) may not express any of these diseases throughout their life. [1][2][3][4]6 After the discovery of lung emphysema associated with severe AATD by Laurell and Erickson 7 more than half a century ago, the PiMZ genotype has been considered by some authors as an AAT moderately deficient genotype with little or no risk. [8][9][10][11] However, later studies indicated that while non-smoking MZs are not at increased risk for lung disease, MZ smokers have an increased risk of developing COPD.…”

“…Conclusion(1) There are an impressive number of MZ carriers (between 2% and 4% of the population of European heritage), living in Europe; America, Australia and New Zealand countries with high smoking rate, and a smaller but not negligible number in other African, Asian and Central and South American countries, where apart from smoking, indoor, outdoor and industrial pollution can play an important role in the development of COPD (2). The biological mechanisms that underlie increased risk among MZs are only partially known, and therefore more studies are needed to know what the contribution of the genetic defect and of the exogenous factors is, together and separately, in the development of COPD in MZ carriers to know the exact risk that this genotype carries, ideally through reference centers 60.…”

The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients

“…Various mutations have been identified that cause reduced serum levels of AAT, and the most common mutations are the missense mutations (Glu342Lys) Z and (Glu264Val) S. These mutations result in serum AAT concentrations of 15% in patients with homozygous ZZ mutations and 33.3% of normal levels in heterozygous SZ mutations, respectively [ 1 ]. Very low circulating AAT levels can be caused by mutants with a stop codon in SERPINA1 (null alleles, like Q 0Bellingham ) or by mutants coding for synthesis of a misfolded protein that is rapidly degraded by the endoplasmic reticulum (ER)-associated machinery (M-like alleles, such as M Procida [ 2 ] and M Heerlen [ 3 ]). Previously, we showed that serum levels of AAT are correlated with the severity of emphysema [ 4 ].…”