Deficiency Mutations of Alpha-1 Antitrypsin. Effects on Folding, Function, and Polymerization

American Journal of Respiratory Cell and Molecular Biology
Imran HaqDavid A Lomas

Abstract

Misfolding, polymerization, and defective secretion of functional alpha-1 antitrypsin underlies the predisposition to severe liver and lung disease in alpha-1 antitrypsin deficiency. We have identified a novel (Ala336Pro, Baghdad) deficiency variant and characterized it relative to the wild-type (M) and Glu342Lys (Z) alleles. The index case is a homozygous individual of consanguineous parentage, with levels of circulating alpha-1 antitrypsin in the moderate deficiency range, but is a biochemical phenotype that could not be classified by standard methods. The majority of the protein was present as functionally inactive polymer, and the remaining monomer was 37% active relative to the wild-type protein. These factors combined indicate an 85 to 95% functional deficiency, similar to that seen with ZZ homozygotes. Biochemical, biophysical, and computational studies further defined the molecular basis of this deficiency. These studies demonstrated that native Ala336Pro alpha-1 antitrypsin could populate the polymerogenic intermediate-and therefore polymerize-more readily than either wild-type alpha-1 antitrypsin or the Z variant. In contrast, folding was far less impaired in Ala336Pro alpha-1 antitrypsin than in the Z variant. The da...Continue Reading

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Citations

Apr 2, 2016·Journal of Hepatology·David A LomasBibek Gooptu
Jul 14, 2016·The Biochemical Journal·Neda Motamedi-ShadDavid A Lomas
Jul 24, 2020·JCI Insight·Mattia LaffranchiJames A Irving
Jan 8, 2019·F1000Research·Irina ConboyZachery Robinson
Jun 12, 2019·Pathology Oncology Research : POR·Hajar JaberieFakhraddin Naghibalhossaini
Dec 15, 2020·Nature Communications·Alistair M JaggerDavid A Lomas
Dec 29, 2020·Therapeutics and Clinical Risk Management·Mark QuinnAlice M Turner
Oct 23, 2020·Science Advances·Sarah V FaullDavid A Lomas
Jun 3, 2021·International Journal of Molecular Sciences·Riccardo RonzoniAnnamaria Fra
Jul 25, 2021·International Journal of Molecular Sciences·Monokesh K SenJens R Coorssen

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