The Z (Glu342Lys) variant of α1-antitrypsin is common in populations of North European descent. The mutation causes individual α1-antitrypsin molecules to assemble into polymer chains in the endoplasmic reticulum of hepatocytes. Z homozygotes (PiZZ) have circulating levels of α1-antitrypsin ∼15% of normal and are predisposed to hepatic cirrhosis and severe, early-onset emphysema. The risk of clinically significant disease associated with the heterozygote PiMZ state is minimal. We describe a case phenotyped as PiZZ during family screening, but with surprisingly preserved circulating α1-antitrypsin levels. Genotyping revealed compound heterozygosity for the Z mutation and a novel, “pseudo-Z” mutation. Biochemical and ion-mobility mass spectrometry characterisation of pseudo-Z α1-antitrypsin showed that it readily populated a polymerogenic intermediate state under physiological conditions. Cell biological studies of a series of α1-antitrypsin variants indicated these effects involved disruption of a hydrogen bond stabilising the F-helix-linker region of the protein structure. These data strongly support the hypothesis that stability of this region co-regulates formation of the polymerogenic intermediate. Whilst the intermediate form of pseudo-Z α1-antitrypsin is more stable than that of the true Z variant, the resultant polymers all share a characteristic neoepitope. Pseudo-Z α1-antitrypsin is thus a useful model for in vitro screening of potential lead compounds to bind the polymerogenic intermediate state, improving the ability to develop novel therapies to treat α1-antitrypsin deficiency. Our data predict that the likelihood of severe disease in the PiZ/Pseudo-Z compound heterozygote state will be increased relative to the PiMZ state, but far lower than for PiZZ individuals.
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