The most common α₁AT deficient variants are known as the Z^(E342K) and S^(E264V) mutants, with the Z allele being the major contributor to pulmonary emphysema and liver disease in persons of European ancestry [4]. Protein assays based on isoelectric focusing (IEF) and differing migration patterns are the predominant method for identifying SERPINA1 ‘deficiency’ mutations.

We describe here a novel SERPINA1 mutant from an asymptomatic patient with circulating α₁AT deficiency. A 49 base pair deletion results in a frame-shift at amino acid T379, replacing the last 16 amino acids of α₁AT and adding an additional 24 amino acids through partial translation of the 3′ UTR. Intracellular accumulation and failed secretion of the α₁AT^T379Δ mutant in cultured cells is consistent with clinical observation of low circulating α₁AT in the patient and establishes the mutation, along with the Z, S and Mm variants, as a bone fide pathogenic variant. Importantly, this represents the first pathogenic mutation identified in the C-terminal domain of α₁AT, which was recently implicated in the formation of pathogenic α₁AT polymers [11], [12]. Normal circulating levels of α₁AT range from 104 to 276 g/L (20–53 uM). Lung disease associated with diminished neutrophil elastase inhibitory capacity is typically observed in patients with decreased circulating α₁AT (0.36–0.57 g/L (5–11 µM)) [13]. The circulating α₁AT level of 0.58 g/L (11 µM) observed in this patient lies at threshold of this disease-associated range.

The T379Δ mutation occurs in the C-terminal region of α₁AT, quite distinct from the Z^(E342K) and S^(E264V) mutants found commonly in European populations but relatively rarely in African populations [6], [14]. It is noteworthy that the patient was of Middle Eastern descent, and it is highly likely that as yet unidentified deleterious α₁AT mutations exist in other population groups that have not been well studied. Critically, these novel mutants may be missed by commonly used phenotyping approaches, further emphasizing the importance of specific genotype-based assays for accurate classification of mutants and diagnosis of α₁AT deficiency [6], [15]. This point is highlighted by the fact that the patient in this study was originally mistyped by IEF as having a Z/M2 phenotype classification. This study further highlights the significance of rare mutations in clinically relevant α₁AT deficiency.

Serpins are flexible molecules capable of extreme conformational change, making them highly susceptible to polymerization. Polymer-causing mutations (such as the α₁AT Z mutant) influence the folding pathway by increasing the lifetime of a polymergenic folding intermediate. Serpin polymers are favored when secondary structural domain swaps occur at a faster rate than folding into the native state. The various pathological serpin mutants identified to date have been shown to accelerate this domain swapping [11], [12]. Using a monoclonal antibody specific for hepatocellular inclusions of α₁AT, Yakasaki et al [12] recently proposed a mechanism of pathological polymerization involving a C-terminal domain swap, distinct from the accepted model involving an s4As/5A swap. The implication of this observation is that the native state of α₁AT is achieved by rapid folding of the C-terminal domain [16]. However, the exact nature of the toxic form of α₁AT polymers in the liver is yet to be determined and may involve heterogeneous populations of polymers [11]. Although the structural consequences of the T379Δ mutation are not immediately obvious, it is highly significant that the mutation introduces an entirely new, extended C-terminal sequence into α₁AT. This is likely to drastically modify the folding rate of the C-terminal domain of the T379Δ mutant, possibly favoring polymerization.

Interventions modifying the folding pathway of α₁AT might be of therapeutic value in treating both loss and gain of function manifestations of α₁AT deficiency [12]. Indeed, a number of strategies designed to attenuate polymerization are under investigation as potential therapies for α₁AT deficiency, including peptide analogues, chemical chaperones, and small molecule allosteric regulators [13], [17], [18]. Some of these strategies (particularly peptide analogues and allosteric regulators) target specific polymerigenic mutations (e.g. Z^E342K) and so would not necessarily be effective against the T379Δ variant. This further highlights the need to better describe the range of pathogenic α₁AT mutations and for detailed understanding of the exact mechanisms of polymer formation.