Advertisement

Journal of Inherited Metabolic Disease

, Volume 31, Issue 1, pp 21–34 | Cite as

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

  • C. M. Greene
  • S. D. W. Miller
  • T. Carroll
  • C. McLean
  • M. O’Mahony
  • M. W. Lawless
  • S. J. O’Neill
  • C. C. Taggart
  • N. G. McElvaney
Review

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.

Keywords

Endoplasmic Reticulum Stress Unfold Protein Response High Resolution Compute Tomography Human Neutrophil Elastase A1AT Deficiency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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.PubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 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.PubMedGoogle Scholar
  4. 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.PubMedGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 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.PubMedGoogle Scholar
  7. Cadene M, Duranton J, North A, et al (1997) Inhibition of neutrophil serine proteinases by suramin. J Biol Chem 272: 9950–9955.PubMedGoogle Scholar
  8. 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.PubMedGoogle Scholar
  9. 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.PubMedGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. Carrell RW (1986) Alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage. J Clin Invest 78: 1427–1431.PubMedGoogle Scholar
  12. Carrell RW, Lomas DA (2002) Alpha-1-antitrypsin deficiency—a model for conformational diseases. New Engl J Med 346: 45–53.PubMedGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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
  18. 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.PubMedGoogle Scholar
  19. Czaja AJ (1998) Frequency and significance of phenotypes for alpha1-antitrypsin deficiency in type 1 autoimmune hepatitis. Dig Dis Sci 43: 1725–1731.PubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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
  22. 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.PubMedGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. Edwards PD, Bernstein PR (1994) Synthetic inhibitors of elastase. Med Res Rev 14: 127–194.PubMedGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. 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.PubMedGoogle Scholar
  28. Eriksson S (1963) Pulmonary emphysema and alpha-1-antitrypsin deficiency. Acta Med Scand 175: 197–205.CrossRefGoogle Scholar
  29. Flotte TR (2002) Recombinant adeno-associated virus gene therapy for cystic fibrosis and alpha(1)-antitrypsin deficiency. Chest 121: 98–102S.PubMedGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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
  32. 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.PubMedGoogle Scholar
  33. Guest PJ, Hansell DM (1992) High resolution computed tomography (HRCT) in emphysema associated with alpha-1-antitrypsin deficiency. Clin Radiol 45: 260–266.PubMedGoogle Scholar
  34. 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.PubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. Hubbard RC, Crystal RG (1990) Strategies for aerosol therapy of alpha-1-antitrypsin deficiency by the aerosol route. Lung 168: 565–578.PubMedGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. Hutchison DC (1998) Alpha-1 antitrypsin deficiency in Europe: geographical distribution of Pi types S and Z. Respir Med 92: 367–377.PubMedGoogle Scholar
  42. 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.PubMedGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 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.PubMedGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. 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.PubMedGoogle Scholar
  48. Kopito RR (1997) ER quality control: the cytoplasmic connection. Cell 88: 427–430.PubMedGoogle Scholar
  49. 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.PubMedGoogle Scholar
  50. Laurell CB, Eriksson S (1963) The electrophoretic alpha1-globulin pattern of serum in alpha1-antitrypsin deficiency. Scand J Clin Lab Invest 15: 132–140.Google Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.PubMedGoogle Scholar
  53. Lomas DA, Evans DL, Finch JT, et al (1992) The mechanism of Z alpha-1-antitrypsin accumulation in the liver. Nature 357: 605–607.PubMedGoogle Scholar
  54. 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.PubMedGoogle Scholar
  55. 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.PubMedGoogle Scholar
  56. 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.PubMedGoogle Scholar
  57. 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.PubMedGoogle Scholar
  58. Marcus NY, Perlmutter DH (2000) Glucosidase and mannosidase inhibitors mediate increased secretion of mutant alpha1 antitrypsin Z. J Biol Chem 275: 1987–1992.PubMedGoogle Scholar
  59. Massi G (1996) Pathogenesis and pathology of liver disease associated with alpha 1 antitrypsin deficiency. Chest 110: 251S–255S.PubMedGoogle Scholar
  60. 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
  61. 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.PubMedGoogle Scholar
  62. 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.PubMedGoogle Scholar
  63. 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.PubMedGoogle Scholar
  64. Molmenti EP, Perlmutter DH, Rubin DC (1993) Cell-specific expression of alpha 1 antitrypsin in human intestinal epithelium. J Clin Invest 92: 2022–2034.PubMedGoogle Scholar
  65. Mori K (2000) Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101: 451–454.PubMedGoogle Scholar
  66. 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.PubMedGoogle Scholar
  67. 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.PubMedGoogle Scholar
  68. Oda Y, Hosokawa N, Wada I, et al (2003) EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science 299: 1394–1397.PubMedGoogle Scholar
  69. 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.PubMedCrossRefGoogle Scholar
  70. 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.PubMedGoogle Scholar
  71. 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.PubMedGoogle Scholar
  72. 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.PubMedGoogle Scholar
  73. Perlmutter DH (2002) Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury. J Clin Invest 110: 1579–1583.PubMedGoogle Scholar
  74. 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
  75. Pittschieler K (2001) Rare alpha-1-antitrypsin phenotypes and liver-test abnormalities during infancy. Acta Paediatr 90: 406-408.Google Scholar
  76. 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
  77. 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.PubMedGoogle Scholar
  78. 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.PubMedGoogle Scholar
  79. 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
  80. 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.PubMedCrossRefGoogle Scholar
  81. Ranes J, Stoller JK (2005) A review of alpha-1 antitrypsin deficiency. Semin Respir Crit Care Med 26: 154–166.PubMedGoogle Scholar
  82. 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.PubMedCrossRefGoogle Scholar
  83. Ron D (2002). Translational control in the endoplasmic reticulum stress response. J Clin Invest 110: 1383–1388.PubMedGoogle Scholar
  84. 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.PubMedGoogle Scholar
  85. Rudnick DA, Perlmutter DH (2005) Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatology 42: 514–521.PubMedGoogle Scholar
  86. 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.PubMedGoogle Scholar
  87. Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569: 29–63.PubMedGoogle Scholar
  88. 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.PubMedGoogle Scholar
  89. 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.PubMedGoogle Scholar
  90. 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.PubMedGoogle Scholar
  91. Sharp HL, Mathis R, Krivit W, et al (1971) The liver in noncirrhotic alpha-1-antitrypsin deficiency. J Lab Clin Med 78: 1012–1013.PubMedGoogle Scholar
  92. 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.PubMedGoogle Scholar
  93. 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.PubMedGoogle Scholar
  94. 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
  95. 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.PubMedGoogle Scholar
  96. 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.PubMedGoogle Scholar
  97. Sveger T (1976) Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 294: 1316–1321.PubMedCrossRefGoogle Scholar
  98. Sveger T, Eriksson S (1995) The liver in adolescents with alpha 1-antitrypsin deficiency. Hepatology 22: 514–517.PubMedGoogle Scholar
  99. 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.PubMedGoogle Scholar
  100. 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: G39–48Google Scholar
  101. 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.Google Scholar
  102. 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.PubMedGoogle Scholar
  103. 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.PubMedGoogle Scholar
  104. 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.PubMedCrossRefGoogle Scholar
  105. 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.PubMedGoogle Scholar
  106. 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.PubMedGoogle Scholar
  107. 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.PubMedCrossRefGoogle Scholar
  108. 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.PubMedGoogle Scholar
  109. 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.Google Scholar
  110. 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.PubMedGoogle Scholar
  111. 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.PubMedGoogle Scholar
  112. Ziomek CA (1998) Commercialization of proteins produced in the mammary gland. Theriogenology 49: 139–144.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • C. M. Greene
    • 1
  • S. D. W. Miller
    • 1
  • T. Carroll
    • 1
  • C. McLean
    • 1
  • M. O’Mahony
    • 1
  • M. W. Lawless
    • 1
    • 2
  • S. J. O’Neill
    • 1
  • C. C. Taggart
    • 1
    • 3
  • N. G. McElvaney
    • 1
  1. 1.Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research CentreBeaumont HospitalDublin 9Ireland
  2. 2.Hepatology Research Division, Institute of Molecular Medicine, Trinity Health Science Building, Trinity CollegeSt. James HospitalDublin 8Ireland
  3. 3.School of Medicine and DentistryQueen’s University BelfastBelfastNorthern Ireland

Personalised recommendations