Three new alpha1-antitrypsin deficiency variants help to define a C-terminal region regulating conformational change and polymerization.

PloS One
Anna M FraLuisa Schiaffonati

Abstract

Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening 'latch' interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency varian...Continue Reading

References

Nov 1, 1996·Nature Structural Biology·P R ElliottD A Lomas
Jan 1, 1997·Protein Science : a Publication of the Protein Society·W S ChangM R Wardell
Mar 27, 1999·The Journal of Biological Chemistry·T R DaffornD A Lomas
Apr 9, 1999·The Journal of Clinical Investigation·R MahadevaD A Lomas
Dec 5, 2002·The Journal of Clinical Investigation·David H Perlmutter
Jun 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Ying WuRichard N Sifers
Apr 20, 2004·The Journal of Biological Chemistry·Elena MirandaDavid A Lomas
Aug 24, 2004·Diagnostic Molecular Pathology : the American Journal of Surgical Pathology, Part B·Ilaria FerrarottiMaurizio Luisetti
Jun 28, 2005·Lancet·James K Stoller, Loutfi S Aboussouan
Mar 17, 2006·Biochemical and Biophysical Research Communications·Min-Jung KimHana Im
Apr 28, 2006·Clinical Chemistry·Marina GorriniMaurizio Luisetti
Jun 2, 2006·Genome Biology·Ruby H P LawJames C Whisstock
Oct 30, 2007·Translational Research : the Journal of Laboratory and Clinical Medicine·Ilaria FerrarottiMaurizio Luisetti
Feb 28, 2009·Annual Review of Biochemistry·Bibek Gooptu, David A Lomas
May 14, 2009·Human Mutation·Daniela MedicinaLuisa Schiaffonati
Jun 26, 2009·The New England Journal of Medicine·Edwin K Silverman, Robert A Sandhaus
Jun 29, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Elena MirandaDavid A Lomas
Sep 22, 2010·Proceedings of the National Academy of Sciences of the United States of America·Ugo I EkeowaDavid A Lomas
Dec 1, 2010·Methods : a Companion to Methods in Enzymology·Didier BelorgeyDavid A Lomas
Oct 20, 2014·Nature Structural & Molecular Biology·Ines A EhrnstorferRaimund Dutzler

❮ Previous
Next ❯

Citations

Nov 27, 2014·Orphanet Journal of Rare Diseases·Ilaria FerrarottiMaurizio Luisetti
Dec 10, 2015·Human Molecular Genetics·Riccardo RonzoniAnna Maria Fra
Nov 14, 2014·Revue des maladies respiratoires·S OttavianiM Luisetti
Jan 6, 2017·Respiratory Medicine Case Reports·Camille de SeynesC Raherison
Jan 1, 2014·Trends in Molecular Medicine·Bibek GooptuDavid A Lomas
Mar 15, 2018·Human Molecular Genetics·Mattia LaffranchiAnnamaria Fra
Mar 3, 2018·Biological Chemistry·Karen JülicherReto Eggenschwiler
Dec 13, 2017·American Journal of Respiratory Cell and Molecular Biology·Nerea MatamalaBeatriz Martinez-Delgado
Feb 6, 2016·The European Respiratory Journal·Annamaria FraElena Miranda
Mar 12, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Adriana OrdóñezDavid A Lomas
Jun 10, 2020·American Journal of Respiratory Cell and Molecular Biology·Nerea MatamalaBeatriz Martinez-Delgado
May 18, 2018·Orphanet Journal of Rare Diseases·Francesco CalleaEmanuele Bellacchio
Oct 23, 2020·Science Advances·Sarah V FaullDavid A Lomas
Mar 7, 2021·Clinical Chemistry and Laboratory Medicine : CCLM·Alice M BalderacchiIlaria Ferrarotti
Apr 2, 2021·The Application of Clinical Genetics·Susana Seixas, Patricia Isabel Marques
Jun 3, 2021·International Journal of Molecular Sciences·Riccardo RonzoniAnnamaria Fra

❮ Previous
Next ❯

Methods Mentioned

BETA
Dot blot
transfection
transfections
dot-blot
dot
ELISA

Software Mentioned

ClustalW2
Jalview
GraphPad Prism

Related Concepts

Related Feeds

Carcinoma, Hepatocellular

Hepatocellular Carcinoma is a malignant cancer in liver epithelial cells. Discover the latest research on Hepatocellular Carcinoma here.

Adrenocortical Carcinoma

Hepatocellular carcinoma is the most common type of primary liver cancer and frequently occurs in individuals with chronic liver diseases like cirrhosis. Here is the latest research.