Skip to main content

Alpha-1 antitrypsin deficiency: A conformational disease associated with lung and liver manifestations

Summary

Alpha-1 antitrypsin (A1AT) is a serine anti-protease produced chiefly by the liver. A1AT deficiency is a genetic disorder characterized by serum levels of less than 11 μmol/L and is associated with liver and lung manifestations. The liver disease, which occurs in up to 15% of A1AT-deficient individuals, is a result of toxic gain-of-function mutations in the A1AT gene, which cause the A1AT protein to fold aberrantly and accumulate in the endoplasmic reticulum of hepatocytes. The lung disease is associated with loss-of-function, specifically decreased anti-protease protection on the airway epithelial surface. The so-called ‘Z’ mutation in A1AT deficiency encodes a glutamic acid-to-lysine substitution at position 342 in A1AT and is the most common A1AT allele associated with disease. Here we review the current understanding of the molecular pathogenesis of A1AT deficiency and the best clinical management protocols.

This is a preview of subscription content, access via your institution.

References

  • Banner BF, Karamitsios N, Smith L, et al (1998) Enhanced phenotypic expression of alpha-1-antitrypsin deficiency in an MZ heterozygote with chronic hepatitis C. Am J Gastroenterol 93: 1541–1545.

    PubMed  CAS  Google Scholar 

  • Bell H, Schrumpf E, Fagerhol MK (1990) Heterozygous MZ alpha-1-antitrypsin deficiency in adults with chronic liver disease. Scand J Gastroenterol 25: 788–792.

    PubMed  CAS  Google Scholar 

  • Bergwitz C, Brabant G, Trautwein C, Manns MP (2002) A patient with autoimmune hepatitis type I, Addison's disease, atrophic thyroiditis, atrophic gastritis, exocrine pancreatic insufficiency, and heterozygous alpha1-antitrypsin deficiency. Am J Gastroenterol 97: 1050–1052.

    PubMed  CAS  Google Scholar 

  • Bowlus CL, Willner I, Zern MA, et al (2005) Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency. Clin Gastroenterol Hepatol 3: 390–396.

    PubMed  CAS  Google Scholar 

  • Brantly ML, Paul LD, Miller BH, et al (1988) Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis 138: 327–336.

    PubMed  CAS  Google Scholar 

  • Burrows JA, Willis LK, Perlmutter DH (2000) Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci U S A 97: 1796–1801.

    PubMed  CAS  Google Scholar 

  • Cadene M, Duranton J, North A, et al (1997) Inhibition of neutrophil serine proteinases by suramin. J Biol Chem 272: 9950–9955.

    PubMed  CAS  Google Scholar 

  • Cantor JO, Cerreta JM, Keller S, et al (1995) Modulation of airspace enlargement in elastase-induced emphysema by intratracheal instillment of hyaluronidase and hyaluronic acid. Exp Lung Res 21: 423–436.

    PubMed  CAS  Google Scholar 

  • Cantor JO, Cerrata JM, Armand G, et al (1998) Aerosolized hyaluronic acid decreases alveolar injury induced by human neutrophil elastase. Proc Soc Exp Biol Med 217: 471–475.

    PubMed  CAS  Google Scholar 

  • Carlson JA, Rogers BB, Sifers RN, et al (1988) Multiple tissues express alpha 1 antitrypsin in transgenic mice and man. J Clin Invest 82: 26–36.

    PubMed  CAS  Article  Google Scholar 

  • Carrell RW (1986) Alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage. J Clin Invest 78: 1427–1431.

    PubMed  CAS  Google Scholar 

  • Carrell RW, Lomas DA (2002) Alpha-1-antitrypsin deficiency—a model for conformational diseases. New Engl J Med 346: 45–53.

    PubMed  CAS  Google Scholar 

  • Casolaro MA, Fells G, Wewers M, et al (1987) Augmentation of lung antineutrophil elastase capacity with recombinant human alpha-1-antitrypsin. J Appl Physiol 63: 2015–2023.

    PubMed  CAS  Google Scholar 

  • Cox DW (1999) α1-antitrypsin deficiency. In: Scriver CR, Beaudet AL, Sly WS et al, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, 2409–2437.

    Google Scholar 

  • Cox DW, Mansfield T (1987) Prenatal diagnosis of alpha-1 antitrypsin deficiency and estimates of fetal risk for disease. J Med Genet 24: 52–59.

    PubMed  CAS  Google Scholar 

  • Cruz PE, Mueller C, Cossette TL, et al (2007) In vivo post-transcriptional gene silencing of alpha-1 antitrypsin by adeno-associated virus vectors expressing siRNA. Lab Invest 87: 893–902.

    PubMed  CAS  Google Scholar 

  • Crystal RG (1998) Alpha-1-antitrypsin deficiency, emphysema and liver disease: genetic basis and strategies for therapy. J Clin Invest 85: 1343–1352.

    Google Scholar 

  • Curiel DT, Chytil A, Courtney M, et al (1989) Serum alpha-1-antitrypsin deficiency associated with the common S-type (glu264-to-val) mutation results from intracellular degradation of alpha-1-antitrypsin prior to secretion. J Biol Chem 264: 10477–10486.

    PubMed  CAS  Google Scholar 

  • Czaja AJ (1998) Frequency and significance of phenotypes for alpha1-antitrypsin deficiency in type 1 autoimmune hepatitis. Dig Dis Sci 43: 1725–1731.

    PubMed  CAS  Google Scholar 

  • Darlington GJ, Astrin KH, Muirhead SP, et al (1982) Assignment of human alpha 1 antitrypsin to chromosome 14 by somatic cell hybrid analysis. Proc Natl Acad Sci U S A 79: 870–873.

    PubMed  CAS  Google Scholar 

  • Dawson LJ, Guest PJ, Stockley RA (2002) The relationship of chronic sputum expectoration to physiologic, radiologic, and ealth status characteristics in alpha(1)-antitrypsin deficiency (PiZ). Chest 122: 1247–1255.

    Google Scholar 

  • de Serres FJ (2002) Worldwide racial and ethnic distribution of 1-antitrypsin deficiency. Summary of an analysis of published genetic epidemiology surveys. Chest 122: 1818–1829.

    PubMed  Google Scholar 

  • Devlin GL, Parfrey H, Tew DJ, Lomas DA, Bottomley SP (2001) Prevention of polymerization of M and Z alpha1-Antitrypsin (alpha1-AT) with trimethylamine N-oxide. Implications for the treatment of alpha1-at deficiency. Am J Respir Cell Mol Biol 24: 727–732.

    PubMed  CAS  Google Scholar 

  • Edwards PD, Bernstein PR (1994) Synthetic inhibitors of elastase. Med Res Rev 14: 127–194.

    PubMed  CAS  Google Scholar 

  • Eigenbrodt ML, McCashland TM, Dy RM, Clark J, Galati J (1997) Heterozygous alpha 1-antitrypsin phenotypes in patients with end stage liver disease. Am J Gastroenterol 92: 602–607.

    PubMed  CAS  Google Scholar 

  • Elliott PR, Bilton D, Lomas DA (1998) Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema. Am J Respir Cell Mol Biol 18: 670–674.

    PubMed  CAS  Google Scholar 

  • Elzouki AN, Verbaan H, Lindgren S, Widell A, Carlson J, Eriksson S (1997) Serine protease inhibitors in patients with chronic viral hepatitis. J Hepatol 27: 42–48.

    PubMed  CAS  Google Scholar 

  • Eriksson S (1963) Pulmonary emphysema and alpha-1-antitrypsin deficiency. Acta Med Scand 175: 197–205.

    Article  Google Scholar 

  • Flotte TR (2002) Recombinant adeno-associated virus gene therapy for cystic fibrosis and alpha(1)-antitrypsin deficiency. Chest 121: 98–102S.

    PubMed  CAS  Google Scholar 

  • Fraizer GC, Harrold TR, Hofker MH, et al (1989) In-frame single codon deletion in the M(Malton) deficiency allele of alpha-1-antitrypsin. Am J Hum Genet 44: 894–902.

    PubMed  CAS  Google Scholar 

  • Gadek JE, Crystal RG (1983) Alpha 1-Antitrypsin deficiency. In: Stanbury JB, Wyngaarden JB, Frederickson DS, et al, eds. The Metabolic Basis of Inherited Disease. New York: McGraw Hill, 1450–1467.

    Google Scholar 

  • Gishen P, Saunders AJS, Tobin MJ, et al (1982) Alpha-1 antitrypsin deficiency: the radiological features of pulmonary emphysema in subjects of Pi-type Z and Pi-type SZ: A survey by the British Thoracic Association. Clin Radiol 33: 371–377.

    PubMed  CAS  Google Scholar 

  • Guest PJ, Hansell DM (1992) High resolution computed tomography (HRCT) in emphysema associated with alpha-1-antitrypsin deficiency. Clin Radiol 45: 260–266.

    PubMed  CAS  Google Scholar 

  • Harding HP, Zhang Y, Bertolotti A, et al (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5: 897–904.

    PubMed  CAS  Google Scholar 

  • Harding HP, Calfon M, Urano F, et al (2002) Transcriptional and translational control in the Mammalian unfolded protein response. Annu Rev Cell Dev Biol 18: 575–599.

    PubMed  CAS  Google Scholar 

  • Hidvegi T, Schmidt BZ, Hale P, et al (2005) Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response. J Biol Chem 280: 39002–39015.

    PubMed  CAS  Google Scholar 

  • Hinds R, Hadchouel A, Shanmugham NP, et al (2006) Variable degree of liver involvement in siblings with PiZZ alpha-1-antitrypsin deficiency-related liver disease. J Pediatr Gastroenterol Nutr 43: 136–138.

    PubMed  CAS  Google Scholar 

  • Hosokawa N, Tremblay LO, You Z, et al (2003) Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong alpha1-antitrypsin by human ER mannosidase I. J Biol Chem 278: 26287–26294.

    PubMed  CAS  Google Scholar 

  • Hubbard RC, Crystal RG (1990) Strategies for aerosol therapy of alpha-1-antitrypsin deficiency by the aerosol route. Lung 168: 565–578.

    PubMed  CAS  Google Scholar 

  • Hubbard RC, Brantly ML, Sellers SE, et al (1989) Anti-neturophil elastase defenses of the lower respiratory tract in alpha 1-antitrypsin deficiency directly augmented with an aerosol of alpha 1-antitrypsin. Ann Intern Med 111: 206–212.

    PubMed  CAS  Google Scholar 

  • Hutchison DC (1998) Alpha-1 antitrypsin deficiency in Europe: geographical distribution of Pi types S and Z. Respir Med 92: 367–377.

    PubMed  CAS  Google Scholar 

  • Janciauskiene S, Dominaitiene R, Sternby NH, et al (2002) Detection of circulating and endothelial cell polymers of Z and wild type alpha 1-antitrypsin by a monoclonal antibody. J Biol Chem 277: 26540–26546.

    PubMed  CAS  Google Scholar 

  • Janciauskiene S, Larsson S, Larsson P, et al (2004) Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by alpha1-antitrypsin. Biochem Biophys Res Commun 321: 592–600.

    PubMed  CAS  Google Scholar 

  • Jiang HY, Wek SA, McGrath BC, et al (2004) Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol 24: 1365–1377.

    PubMed  CAS  Google Scholar 

  • Kawabata K, Suzuki M, Sugitani M, et al (1991) ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem Biophys Res Commun 177: 814–820.

    PubMed  CAS  Google Scholar 

  • Knorre A, Wagner M, Schaefer HE, et al (2002) DeltaF508-CFTR causes constitutive NF-kappaB activation through an ER-overload response in cystic fibrosis lungs. Biol Chem 383: 271–282.

    PubMed  CAS  Google Scholar 

  • Kok KF, Wahab PJ, Houwen RH, et al (2007) Heterozygous alpha-I antitrypsin deficiency as a co-factor in the development of chronic liver disease: a review. Neth J Med 65: 160–166.

    PubMed  CAS  Google Scholar 

  • Kopito RR (1997) ER quality control: the cytoplasmic connection. Cell 88: 427–430.

    PubMed  CAS  Google Scholar 

  • Kudo T, Katayama T, Imaizumi K, et al (2002) The unfolded protein response is involved in the pathology of Alzheimer’s disease. Ann N Y Acad Sci 977: 349–355.

    PubMed  CAS  Google Scholar 

  • Laurell CB, Eriksson S (1963) The electrophoretic alpha1-globulin pattern of serum in alpha1-antitrypsin deficiency. Scand J Clin Lab Invest 15: 132–140.

    CAS  Google Scholar 

  • Lawless MW, Greene CM, Mulgrew A, et al (2004) Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency. J Immunol 172: 5722–5726.

    PubMed  CAS  Google Scholar 

  • Lawless MW, Mankan AK, White M, et al (2007) Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses. BMC Cell Biol 8: 30.

    PubMed  Google Scholar 

  • Lomas DA, Evans DL, Finch JT, et al (1992) The mechanism of Z alpha-1-antitrypsin accumulation in the liver. Nature 357: 605–607.

    PubMed  CAS  Google Scholar 

  • Luisetti M, Sturani C, Sella D, et al (1996) MR889, a neutrophil elastase inhibitor, in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled clinical trial. Eur Respir J 9: 1482–1486.

    PubMed  CAS  Google Scholar 

  • Ma Y, Brewer JW, Diehl JA, et al (2002) Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol 318: 1351–1365.

    PubMed  CAS  Google Scholar 

  • Mahadeva R, Dafforn TR, Carrell RW, et al (2002) 6-Mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerization. Implications for the prevention of Z alpha(1)-antitrypsin-related cirrhosis. J Biol Chem 277: 6771–6774.

    PubMed  CAS  Google Scholar 

  • Mao JT, Goldin JG, Dermand J, et al (2002) A pilot study of all-trans-retinoic acid for the treatment of human emphysema. Am J Respir Crit Care Med 165: 718–723.

    PubMed  Google Scholar 

  • Marcus NY, Perlmutter DH (2000) Glucosidase and mannosidase inhibitors mediate increased secretion of mutant alpha1 antitrypsin Z. J Biol Chem 275: 1987–1992.

    PubMed  CAS  Google Scholar 

  • Massi G (1996) Pathogenesis and pathology of liver disease associated with alpha 1 antitrypsin deficiency. Chest 110: 251S–255S.

    PubMed  CAS  Google Scholar 

  • McElvaney NG, Feuerstein I, Simon TR, et al (1989) Comparison of the relative sensitivity of routine pulmonary function tests, scintigraphy, and computerised axial tomography in detecting early lung disease associated with α1-antitrypsin deficiency. Am Rev Respir Dis 139: A122.

    Google Scholar 

  • McElvaney NG, Stoller JK, Buist AS, et al (1997) Baseline characteristics of enrolees in the National Heart, Lung and Blood Institute Registry of alpha-1-antitrypsin deficiency. Alpha 1-Antitrypsin Deficiency Registry Study Group. Chest 111: 394–403.

    PubMed  CAS  Google Scholar 

  • Miller SD, Greene CM, McLean C, et al (2007) Tauroursodeoxycholic acid inhibits apoptosis induced by Z alpha-1 antitrypsin via inhibition of bad. Hepatology 46: 496–503.

    PubMed  CAS  Google Scholar 

  • Miranda E, Romisch K, Lomas DA (2004) Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum. J Biol Chem 279: 28283–28291.

    PubMed  CAS  Google Scholar 

  • Molmenti EP, Perlmutter DH, Rubin DC (1993) Cell-specific expression of alpha 1 antitrypsin in human intestinal epithelium. J Clin Invest 92: 2022–2034.

    PubMed  CAS  Google Scholar 

  • Mori K (2000) Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101: 451–454.

    PubMed  CAS  Google Scholar 

  • Mulgrew AT, Taggart CC, Lawless MW, et al (2004) Z alpha1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant. Chest 125: 1952–1957.

    PubMed  CAS  Google Scholar 

  • Novoradovskaya N, Lee J, Yu ZX, et al (1998) Inhibition of intracellular degradation increases secretion of a mutant form of alpha1-antitrypsin associated with profound deficiency. J Clin Invest 101: 2693–2701.

    PubMed  CAS  Google Scholar 

  • Oda Y, Hosokawa N, Wada I, et al (2003) EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science 299: 1394–1397.

    PubMed  CAS  Google Scholar 

  • Owen MC, Brennan SO, Lewis JH, et al (1983) Mutation of antitrypsin to antithrombin -1 antitrypsin Pittsburgh (358-Met Arg), a fatal bleeding disorder. N Engl J Med 309: 694–698.

    PubMed  CAS  Article  Google Scholar 

  • Ozaki I, Zern MA, Liu S, Wei DL, Pomerantz RJ, Duan L (1999) Ribozyme-mediated specific gene replacement of the alpha1-antitrypsin gene in human hepatoma cells. J Hepatol 31: 53–60.

    PubMed  CAS  Google Scholar 

  • Parfrey H, Mahadeva R, Ravenhill NA, et al (2003) Targeting a surface cavity of alpha 1-antitrypsin to prevent conformational disease. J Biol Chem 278: 33060–33066.

    PubMed  CAS  Google Scholar 

  • Pauwels RA, Buist AS, Calverley PM, et al (2001) Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med 163: 1256–1276.

    PubMed  CAS  Google Scholar 

  • Perlmutter DH (2002) Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury. J Clin Invest 110: 1579–1583.

    PubMed  CAS  Google Scholar 

  • Piitulainen E, Sveger T (2002) Respiratory symptoms and lung function in young adults with severe alpha(1)-antitrypsin deficiency (PiZZ). Thorax 57: 705–708.

    Google Scholar 

  • Pittschieler K (2001) Rare alpha-1-antitrypsin phenotypes and liver-test abnormalities during infancy. Acta Paediatr 90: 406-408.

    Google Scholar 

  • Pittulainen E, Carlson J, Ohlsson K, Sveger T (2005) Alpha-1 antitrypsin deficiency in 26-year-old subjects: lung, liver, and protease/protease inhibitor studies. Chest 128: 2076–2081.

    Google Scholar 

  • Propst T, Propst A, Dietze O, Judmaier G, Braunsteiner H, Vogel W (1992) High prevalence of viral infection in adults with homozygous and heterozygous alpha 1-antitrypsin deficiency and chronic liver disease. Ann Intern Med 117: 641–645.

    PubMed  CAS  Google Scholar 

  • Psacharopoulos HT, Mowat AP, Cook PJ, et al (1983) Outcome of liver disease associated with alpha-1- antitrypsin deficiency (PiZ). Implications for genetic counselling and antenatal diagnosis. Arch Dis Child 58: 882–887.

    PubMed  CAS  Google Scholar 

  • Rakela J, Goldschmiedt M, Ludwig J (1987) Late manifestation of chronic liver disease in adults with alpha-1-antitrypsin deficiency. Dig Dis Sci 32: 1358-1362.

    Google Scholar 

  • Ralston DR, Marsh CB, Lowe MP, et al (1997) Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release. Role of surface proteinase-3, alpha1-antitrypsin, and Fcgamma receptors. J Clin Invest 100: 1416–1424.

    PubMed  CAS  Article  Google Scholar 

  • Ranes J, Stoller JK (2005) A review of alpha-1 antitrypsin deficiency. Semin Respir Crit Care Med 26: 154–166.

    PubMed  Google Scholar 

  • Rogers J, Kalsheker N, Wallis S, et al (1983) The isolation of a clone for human alpha 1-antitrypsin and the detection of alpha 1-antitrypsin in mRNA from liver and leukocytes. Biochem Biophys Res Commun 116: 375–382.

    PubMed  CAS  Article  Google Scholar 

  • Ron D (2002). Translational control in the endoplasmic reticulum stress response. J Clin Invest 110: 1383–1388.

    PubMed  CAS  Google Scholar 

  • Rouhani F, Paone G, Smith NK, et al (2000) Lung neutrophil burden correlates with increased pro-inflammatory cytokines and decreased lung function in individuals with alpha(1)-antitrypsin deficiency. Chest 117: 250S–251S.

    PubMed  Google Scholar 

  • Rudnick DA, Perlmutter DH (2005) Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatology 42: 514–521.

    PubMed  CAS  Google Scholar 

  • Schmidt BZ, Perlmutter DH (2005) Grp78, Grp94, and Grp170 interact with alpha1-antitrypsin mutants that are retained in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol 289: G444–455.

    PubMed  CAS  Google Scholar 

  • Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569: 29–63.

    PubMed  Google Scholar 

  • Schroeder WT, Miller MF, Woo SL, et al (1985) Chromosomal localization of the human alpha 1-antitrypsin gene (PI) to 14q31–32. Am J Hum Genet 37: 868–872.

    PubMed  CAS  Google Scholar 

  • Scott BB, Egner W (2006) Does alpha1-antitrypsin phenotype PiMZ increase the risk of fibrosis in liver disease due to hepatitis C virus infection? Eur J Gastroenterol Hepatol 18: 521–523.

    PubMed  CAS  Google Scholar 

  • Sharp HL, Bridges RA, Krivit W, et al (1969) Cirrhosis associated with alpha-1 antitrypsin deficiency: a previously unrecognized inherited disorder. J Lab Clin Med 73: 934–939.

    PubMed  CAS  Google Scholar 

  • Sharp HL, Mathis R, Krivit W, et al (1971) The liver in noncirrhotic alpha-1-antitrypsin deficiency. J Lab Clin Med 78: 1012–1013.

    PubMed  CAS  Google Scholar 

  • Sharp LK, Mallya M, Kinghorn KJ, et al (2006) Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis. FEBS J 273: 2540–2552.

    PubMed  CAS  Google Scholar 

  • Silverman EK, Pierce JA, Province MA, et al (1989) Variability of pulmonary function in alpha-1-antitrypsin deficiency: clinical correlates. Ann Intern Med 111: 982–991.

    PubMed  CAS  Google Scholar 

  • Simon TR, McElvaney NG, Feuerstein I, et al (1989) Quantitative comparison of V-Q and CT for identifying emphysema in α1-antitrypsin deficiency. J Nucl Med 30: 10.

    Google Scholar 

  • Sokol RJ, Balistreri WF, Hoofnagle JH, et al (1985) Vitamin E deficiency in adults with chronic liver disease. Am J Clin Nutr 41: 66–72.

    PubMed  CAS  Google Scholar 

  • Song S, Morgan M, Ellis T, et al (1998) Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc Natl Acad Sci U S A 95: 14384–14388.

    PubMed  CAS  Google Scholar 

  • Sveger T (1976) Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 294: 1316–1321.

    PubMed  CAS  Article  Google Scholar 

  • Sveger T, Eriksson S (1995) The liver in adolescents with alpha 1-antitrypsin deficiency. Hepatology 22: 514–517.

    PubMed  CAS  Google Scholar 

  • Teckman JH, Perlmutter DH (2000) Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol Gastrointest Liver Physiol 279: G961–974.

    PubMed  CAS  Google Scholar 

  • Teckman JH, Gilmore R, Perlmutter DH (2001a) Role of ubiquitin in proteasomal degradation of mutant alpha(1)-antitrypsin Z in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol. 278: G39–48

    Google Scholar 

  • Teckman JH, Burrows J, Hidvegi T, Schmidt B, Hale PD, Perlmutter DH (2001b) The proteasome participates in degradation of mutant alpha 1-antitrypsin Z in the endoplasmic reticulum of hepatoma-derived hepatocytes. J Biol Chem 276: 44865–44872.

    CAS  Google Scholar 

  • Teckman JH, An JK, Loethen S, et al (2002) Fasting in alpha1-antitrypsin deficient liver: constitutive activation of autophagy. Am J Physiol Gastrointest Liver Physiol 283: G1156–1165.

    PubMed  CAS  Google Scholar 

  • Teckman JH, An JK, Blomenkamp K, et al (2004) Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol 286: G851–862.

    PubMed  CAS  Google Scholar 

  • Tobin MJ, Cook PJL, Hutchinson DC (1983) Alpha-1-antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. Br J Dis Chest 77: 14–27.

    PubMed  CAS  Article  Google Scholar 

  • Travers KJ, Patil CK, Wodicka L, et al (2000) Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101: 249–258.

    PubMed  CAS  Google Scholar 

  • Wall M, Moe E, Eisenberg J, et al (1990) Long term follow up of a cohort of children with alpha-1-antitrypsin deficiency. J Pediatr 116: 248–251.

    PubMed  CAS  Google Scholar 

  • Wewers MD, Casolaro MA, Sellers SE, et al (1987) Replacement therapy for alpha1-antitrypsin deficiency associated with emphysema. N Engl J Med 316: 1055–1062.

    PubMed  CAS  Article  Google Scholar 

  • Williams JC, Falcone RC, Knee C, et al (1991) Biologic characterization of ICI200,800 and ICI 200,355, novel inhibitors of human neutrophil elastase. Am Rev Respir Dis 144: 875–883.

    PubMed  CAS  Google Scholar 

  • Wright G, Carver A, Cottom D, et al (1991) High level expression of active human alpha-1-antitrypsin in the milk of transgenic sheep. Biotechnology (NY) 9: 830–834.

    CAS  Google Scholar 

  • Yoshida H, Matsui T, Yamamoto A, et al (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107: 881–891.

    PubMed  CAS  Google Scholar 

  • Yoshida H, Matsui T, Hosokawa N, et al (2003) A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell 4: 265–271.

    PubMed  CAS  Google Scholar 

  • Ziomek CA (1998) Commercialization of proteins produced in the mammary gland. Theriogenology 49: 139–144.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C. M. Greene.

Additional information

Communicating editor: Guy Besley

Competing interests: None declared

References to electronic databases: Alpha 1-antitrypsin deficiency: +107400.

C.M. Greene and S.D.W. Miller contributed equally to the work.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Greene, C.M., Miller, S.D.W., Carroll, T. et al. Alpha-1 antitrypsin deficiency: A conformational disease associated with lung and liver manifestations. J Inherit Metab Dis 31, 21–34 (2008). https://doi.org/10.1007/s10545-007-0748-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-007-0748-y

Keywords

  • Endoplasmic Reticulum Stress
  • Unfold Protein Response
  • High Resolution Compute Tomography
  • Human Neutrophil Elastase
  • A1AT Deficiency