Abstract
Lung disease in alpha-1-antitrypsin deficiency (AATD) results from dysregulated proteolytic activity, mainly by neutrophil elastase (HNE), in the lung parenchyma. This is the result of a substantial reduction of circulating alpha-1-antitrypsin (AAT) and the presence in the plasma of inactive polymers of AAT. Moreover, some AAT mutants have reduced intrinsic activity toward HNE, as demonstrated for the common Z mutant, as well as for other rarer variants. Here we report the identification and characterisation of the novel AAT reactive centre loop variant Gly349Arg (p.G373R) present in the ExAC database. This AAT variant is secreted at normal levels in cellular models of AATD but shows a severe reduction in anti-HNE activity. Biochemical and molecular dynamics studies suggest it exhibits unfavourable RCL presentation to cognate proteases and compromised insertion of the RCL into β-sheet A. Identification of a fully dysfunctional AAT mutant that does not show a secretory defect underlines the importance of accurate genotyping of patients with pulmonary AATD manifestations regardless of the presence of normal levels of AAT in the circulation. This subtype of disease is reminiscent of dysfunctional phenotypes in anti-thrombin and C1-inibitor deficiencies so, accordingly, we classify this variant as the first pure functionally-deficient (type II) AATD mutant.
Highlights
Severe alpha-1-antitrypsin deficiency (AATD, MIM #613490) affects approximately 1 in 2000 of the Northern European population
We identified a Gly!Arg mutation at the P10 (349) position that violates the pattern noted for residues in the reactive centre loop (RCL) hinge region [28], and putatively could interfere with inhibitory activity (Fig 2A)
Gly349 is relatively conserved among SERPINA1 orthologues, while within the human serpins the 349 position shows a preference for small aliphatic residues (Fig 2B and S1 File)
Summary
Severe alpha-1-antitrypsin deficiency (AATD, MIM #613490) affects approximately 1 in 2000 of the Northern European population. It is associated with pathogenic variants of the SERPINA1 gene (MIM #107400) which encodes alpha-1-antitrypsin (AAT). AAT is the archetypal member of the serpin superfamily of serine-protease inhibitors [1]; its primary physiological role is to protect the lung parenchyma from attack by the serine proteases neutrophil elastase (HNE), cathepsin G [2] and proteinase 3 [3]. Mutations that reduce AAT plasma levels alter the balance between inhibitory and proteolytic activity leading to early onset emphysema and COPD [4]. A subset of SERPINA1 pathogenic alleles, well-represented by the common severe deficiency Z allele (E342K, p.E366K) can lead to accumulation of the protein as ordered.
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