title: Molecular pathogenesis of alpha-1-antitrypsin deficiency.
abstract: Alpha-1 antitrypsin (α1-AT) is the most abundant circulating protease inhibitor. The common severe Z allele of α1-AT (Glu342Lys) causes the protein to form ordered polymers that are retained within the endoplasmic reticulum of hepatocytes. These polymers form the periodic acid-Schiff positive inclusions that are associated with cirrhosis. The lack of circulating α1-AT predisposes the Z α1-AT homozygote to early onset emphysema. We review here the molecular basis of α1-AT deficiency and show how understanding the liver disease provides new insights in the pathobiology of the associated emphysema. The mechanism of α1-AT deficiency provides a paradigm for a wider group of conditions that we have termed the serpinopathies. We also examine the strategies that are being pursued to develop novel therapies for α1-AT deficiency. This review considers our understanding of the pathobiology of α1-AT deficiency and then illustrate the therapeutic possibilities that can ensue once we understand basic mechanisms of disease.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: A
authors.initials: A
authors.lastname: Duvoix
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: B D
authors.initials: BD
authors.lastname: Roussel
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, UK. Electronic address: dal16@cam.ac.uk.
authors.forename: D A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D000818:Animals; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000515:alpha 1-Antitrypsin / Q000737:chemistry; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D000515:alpha 1-Antitrypsin
keywords: Alpha-1 antitrypsin deficiency; Conformational disease; Défaut de repliement; Déficit en alpha-1 antitrypsine; Liver disease; Maladie hépatique; Maladies conformationnelles; Misfolding; Protein evolution; Évolution protéique