The pathological Trento variant of alpha-1-antitrypsin (E75V) shows nonclassical behaviour during polymerization.

The FEBS Journal
Elena MirandaAnnamaria Fra

Abstract

Severe alpha-1-antitrypsin deficiency (AATD) is most frequently associated with the alpha-1-antitrypsin (AAT) Z variant (E342K). ZZ homozygotes exhibit accumulation of AAT as polymers in the endoplasmic reticulum of hepatocytes. This protein deposition can lead to liver disease, with the resulting low circulating levels of AAT predisposing to early-onset emphysema due to dysregulation of elastinolytic activity in the lungs. An increasing number of rare AAT alleles have been identified in patients with severe AATD, typically in combination with the Z allele. Here we report a new mutation (E75V) in a patient with severe plasma deficiency, which we designate Trento. In contrast to the Z mutant, Trento AAT was secreted efficiently when expressed in cellular models but showed compromised conformational stability. Polyacrylamide gel electrophoresis (PAGE) and ELISA-based analyses of the secreted protein revealed the presence of oligomeric species with electrophoretic and immunorecognition profiles different from those of Z and S (E264V) AAT polymers, including reduced recognition by conformational monoclonal antibodies 2C1 and 4B12. This altered recognition was not due to direct effects on the epitope of the 2C1 monoclonal antibody w...Continue Reading

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Citations

Mar 15, 2018·Human Molecular Genetics·Mattia LaffranchiAnnamaria Fra
Sep 19, 2018·Orphanet Journal of Rare Diseases·Céline RenouxPhilippe Joly
Jul 24, 2020·JCI Insight·Mattia LaffranchiJames A Irving
Jan 10, 2021·International Journal of Molecular Sciences·Sonia ÁguilaIrene Martínez-Martínez
Feb 1, 2021·International Journal of Biological Macromolecules·Shoyab AnsariMohamad Aman Jairajpuri
Dec 6, 2020·International Journal of Molecular Sciences·Urszula LechowiczJoanna Chorostowska-Wynimko
Oct 23, 2020·Science Advances·Sarah V FaullDavid A Lomas
Jun 3, 2021·Materials·Samuele RaccostaMauro Manno
Jun 3, 2021·International Journal of Molecular Sciences·Riccardo RonzoniAnnamaria Fra

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Methods Mentioned

BETA
electrophoresis
bronchoalveolar lavage
glycosylation
ELISA
dot blot
transfection
confocal microscopy
electrophoretic

Software Mentioned

NumPy script
Python
gromacs
ImageJ

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