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α1-Antitrypsin: what it tells us about COPD
S62 Characterisation of a novel “pseudo-Z” variant of α1-antitrypsin
  1. M-P Nyon1,
  2. L Segu1,
  3. B Roussel2,
  4. N Kalsheker3,
  5. D A Lomas2,
  6. K Thalassinos1,
  7. B Gooptu1
  1. 1Institute of Structural and Molecular Biology, University College London and Birkbeck College, University of London, London, UK
  2. 2Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
  3. 3Division of Clinical Chemistry, University Hospital, Queens Medical Centre, Nottingham, UK


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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