Heteropolymerization of α-1-antitrypsin mutants in cell models mimicking heterozygosity

Human Molecular Genetics
Mattia LaffranchiAnnamaria Fra

Abstract

The most common genotype associated with severe α-1-antitrypsin deficiency (AATD) is the Z homozygote. The Z variant (Glu342Lys) of α-1-antitrypsin (AAT) undergoes a conformational change and is retained within the endoplasmic reticulum (ER) of hepatocytes leading to the formation of ordered polymeric chains and inclusion bodies. Accumulation of mutated protein predisposes to cirrhosis whilst plasma AAT deficiency leads to emphysema. Increased risk of liver and lung disease has also been reported in heterozygous subjects who carry Z in association with the milder S allele (Glu264Val) or even with wild-type M. However, it is unknown whether Z AAT can co-polymerize with other AAT variants in vivo. We co-expressed two AAT variants, each modified by a different tag, in cell models that replicate AAT deficiency. We used pull-down assays to investigate interactions between co-expressed variants and showed that Z AAT forms heteropolymers with S and with the rare Mmalton (Phe52del) and Mwurzburg (Pro369Ser) mutants, and to a lesser extent with the wild-type protein. Heteropolymers were recognized by the 2C1 mAb that binds to Z polymers in vivo. There was increased intracellular accumulation of AAT variants when co-expressed with Z AAT,...Continue Reading

References

Jun 10, 1976·The New England Journal of Medicine·T Sveger
Mar 20, 1986·The New England Journal of Medicine·S ErikssonR Velez
Nov 1, 1996·Nature Structural Biology·P R ElliottD A Lomas
Dec 1, 1996·American Journal of Respiratory and Critical Care Medicine·G M TurinoJ K Stoller
Oct 2, 1998·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·I W GraziadeiM K Porayko
Apr 9, 1999·The Journal of Clinical Investigation·R MahadevaD A Lomas
Oct 3, 2003·American Journal of Respiratory and Critical Care Medicine·UNKNOWN American Thoracic Society, UNKNOWN European Respiratory Society
Jan 11, 2007·Journal of Microscopy·S Bolte, F P Cordelières
May 14, 2009·Human Mutation·Daniela MedicinaLuisa Schiaffonati
Jun 29, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Elena MirandaDavid A Lomas
Feb 1, 2012·Therapeutic Advances in Respiratory Disease·Francisco Rodriguez-FriasRosendo Jardi
Dec 1, 2012·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Adriana OrdóñezDavid A Lomas
Feb 13, 2014·European Journal of Gastroenterology & Hepatology·Tessa M CacciottoloWilliam J H Griffiths
Jul 30, 2014·Expert Review of Gastroenterology & Hepatology·Jeffrey H Teckman, Nisha Mangalat
Jul 15, 2015·Methods in Molecular Biology·Sonchita BagchiÅsa Wallén-Mackenzie
Dec 10, 2015·Human Molecular Genetics·Riccardo RonzoniAnna Maria Fra
Feb 6, 2016·The European Respiratory Journal·Annamaria FraElena Miranda
Mar 8, 2016·Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·Andrew S ChuDavid H Perlmutter
Apr 2, 2016·Journal of Hepatology·David A LomasBibek Gooptu
Aug 27, 2016·Annals of the American Thoracic Society·Edwin K Silverman
Sep 8, 2016·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jennifer A DickensStefan J Marciniak

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Citations

Mar 14, 2020·The European Respiratory Journal·Gerard N McElvaneyRobert A Stockley
Jul 24, 2020·JCI Insight·Mattia LaffranchiJames A Irving
May 18, 2019·Scientific Reports·Reto EggenschwilerTobias Cantz
Oct 23, 2020·Science Advances·Sarah V FaullDavid A Lomas
Apr 2, 2021·The Application of Clinical Genetics·Susana Seixas, Patricia Isabel Marques
Jun 3, 2021·International Journal of Molecular Sciences·Riccardo RonzoniAnnamaria Fra
Jul 3, 2021·International Journal of Molecular Sciences·Francesco CalleaEmanuele Bellacchio
Aug 19, 2021·Cellular and Molecular Life Sciences : CMLS·Emanuela D'AcuntoElena Miranda

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