α1-Antitrypsin Deficiency

Liver Disease Associated With Retention of a Mutant Secretory Glycoprotein in the Endoplasmic Reticulum
  • David H. Perlmutter
Part of the Methods in Molecular Biology™ book series (MIMB, volume 232)


The classical form of α1-antitryspsin (α1AT) deficiency, homozygous for the α1ATZ allele, is associated with a mutant protein that is retained in the endoplasmic reticulum (ER) of liver cells rather than secreted into the blood and body fluids. Affected individuals are susceptible to liver injury and hepatocellular carcinoma. Most of the evidence in the literature suggests that liver disease is caused by


Endoplasmic Reticulum Endoplasmic Reticulum Stress Fabry Disease Nephrogenic Diabetes Insipidus Endoplasmic Reticulum Retention 
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.


  1. 1.
    Huber, R. and Carrell, R. W. (1990) Implications of the three-dimensional structure of α-1-antitrypsin for structure and function of serpins. Biochemistry 28, 895–8966.Google Scholar
  2. 2.
    Perlmutter, D. H. (2001) α1-Antitrypsin deficiency, in The Liver: Biology and Pathobiology (Arias, I. M., Boyer, J. L., Fausto, N., Jakoky, W. B., Schachter, D. and Shafritz, D. A., eds.), Raven Press, New York, pp. 699–719.Google Scholar
  3. 3.
    Janoff, A. (1985) Elastases and emphysema: current assessment of the protease-antiprotease hypothesis. Am. Rev. Respir. Dis. 132, 417–433.PubMedGoogle Scholar
  4. 4.
    Crystal, R. G. (1990) Alpha-1-antitrypsin deficiency, emphysema and liver disease: genetic basis and strategies for therapy. J. Clin. Invest. 95, 1343–1352.CrossRefGoogle Scholar
  5. 5.
    Janus, E. D., Phillips, N. T., and Carrell, R. W. (1985) Smoking, lung function and α-1-antitrypsin deficiency. Lancet I, 152–154.CrossRefGoogle Scholar
  6. 6.
    Silverman, E. K., Province, M. A., Rao, D. C., Pierce, J. A., and Campbell, E. J. (1990) A family study of the variability of pulmonary function in α1-antitrypsin deficiency, quantitative phenotypes. Am. Rev. Resp. Dis. 142, 1015–1021.PubMedGoogle Scholar
  7. 7.
    Eriksson, S., Carlson, J., and Velez, R. (1986) Risk of cirrhosis and primary liver cancer in α-1-antitrypsin deficiency. N. Engl. J. Med. 314, 736–739.PubMedCrossRefGoogle Scholar
  8. 8.
    Carlson, J. A., Rogers, B. B., Sifers, R. N., Finegold, M. J., Clift, S. M., DeMayo, F.J., et al. (1989) Accumulation of PiZ antitrypsin causes liver damage in transgenic mice. J. Clin. Invest. 83, 1183–1190.PubMedCrossRefGoogle Scholar
  9. 9.
    Dycaico, M. J., Grant, S. G., Felts, K., Nichols, S. W., Geller, S. A., and Sorge, J. A. (1988) Neonatal hepatitis induced by α-1-antitrypsin: a transgenic mouse model. Science 242, 1409–1412.PubMedCrossRefGoogle Scholar
  10. 10.
    Sveger, T. (1976) Liver disease in α1-antitrypsin deficiency detected by screening of 200,000 infants. N. Engl. J. Med. 294, 1316–1321.PubMedCrossRefGoogle Scholar
  11. 11.
    Sveger, T. (1995) The natural history of liver disease in α-1-antitrypsin deficient children. Acta. Paediatr. Scand. 77, 847–851.CrossRefGoogle Scholar
  12. 12.
    Carrell, R. W. and Lomas, D. A. (1997) Conformational disease. Lancet 350, 134–138.PubMedCrossRefGoogle Scholar
  13. 13.
    Lomas, D. A., Evans, D. L., Finch, J. T., and Carrell, R. W. (1992) The mechanism of Z α1-antitrypsin accumulation in the liver. Nature 357, 605–607.PubMedCrossRefGoogle Scholar
  14. 14.
    Kim, J., Lee, K. N., Yi, G. S., and Yu, M. H. (1995) A thermostable mutation located at the hydrophobic core of α1-antitrypsin suppresses the folding defect of the Z-type variant. J. Biol. Chem. 270, 8597–8601.PubMedCrossRefGoogle Scholar
  15. 15.
    Sidhar, S. K., Lomas, D. A., Carrell, R. W., and Foreman, R. C. (1995) Mutations which impede loop-sheet polymerization enhance the secretion of human α1-an-titrypsin deficiency variants. J. Biol. Chem. 270, 8393–8396.PubMedCrossRefGoogle Scholar
  16. 16.
    Kang, H. A., Lee, K. N., and Yu, M.-H. (1997) Folding and stability of the Z and Siiyama genetic variants of human α1-antitrypsin. J. Biol. Chem. 272, 510–516.PubMedCrossRefGoogle Scholar
  17. 17.
    Davis, R. L., Shrimpton, A. E., Holohan, P. D., Bradshaw, C., Feiglin, D., Collins, G. H., et al. (1999) Familial dementia caused by polymerization of mutant neuroserpin. Nature 401, 376–379.PubMedGoogle Scholar
  18. 18.
    Lin, L., Schmidt, B., Teckman, J., and Perlmutter, D. H. (2001) A naturally occurring non-polymerogenic mutant of α1-antitrypsin characterized by prolonged retention in the endoplasmic reticulum. J. Biol. Chem. 276, 33,893–33,898.PubMedCrossRefGoogle Scholar
  19. 19.
    Burrows, J. A. J., Willis, L. K., and Perlmutter, D. H. (2000) Chemical chaperones mediate increased secretion of mutant a1-antitrypsin (α1-AT) Z. A potential pharmacological strategy for prevention of liver injury and emphysema in α1-AT deficiency. Proc. Natl. Acad. Sci. USA 97, 1796–1801.PubMedCrossRefGoogle Scholar
  20. 20.
    McCracken, A. A. and Brodsky, J. L. (1996) Assembly of ER-associated protein degradation in vitro, dependence on cytosol, calnexin, and ATP. J. Cell. Biol. 132, 291–298.PubMedCrossRefGoogle Scholar
  21. 21.
    Werner, E. D., Brodsky, J. L., and McCracken, A. A. (1996) Proteasome-dependent endoplasmic reticulum-associated protein degradation, an unconventional route to a familiar fate. Proc. Natl. Acad. Sci. USA 93, 13,797–13,801.PubMedCrossRefGoogle Scholar
  22. 22.
    Qu, D., Teckman, J. H., Omura, S., and Perlmutter, D. H. (1996) Degradation of mutant secretory protein, α1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J. Biol. Chem. 271, 22,791–22,795.PubMedCrossRefGoogle Scholar
  23. 23.
    Teckman, J. H., Marcus, N., and Perlmutter, D. H. (2000) The role of ubiquitin in proteasomal degradation of mutant α1-antitrypsin Z in the endoplasmic reticulum. Am. J. Physiol. 278, G39–G48.Google Scholar
  24. 24.
    Teckman, J. H. and Perlmutter, D. H. (2000) Retention of the mutant secretroy protein α1-antitrypsin Z in the endoplasmic reticulum induces autophagy. Am. J. Physiol. 279, G961–G974.Google Scholar
  25. 25.
    Cabral, C. M., Choudhury, P., Liu, Y., and Sifers, R. N. (2000) Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways. J. Biol. Chem. 275, 25,015–25,022.PubMedCrossRefGoogle Scholar
  26. 26.
    Teckman, J. H., Burrows, J., Hidvegi, T., Schmidt, B., Hale, P. D., and Perlmutter, D. H. (2001) The proteasome participants in degradation of mutant α1-antitrypsin Z in the endoplasmic reticulum of hepatoma-derived hepatocytes. J. Biol. Chem. 48, 44,865–44,872.CrossRefGoogle Scholar
  27. 27.
    Mayer, T., Braun, T., and Jentsch, S. (1998) Role of the proteasome in membrane extraction of a shortlived ER-transmembrane protein. EMBO J. 17, 3251–3257.PubMedCrossRefGoogle Scholar
  28. 28.
    Ye, Y., Meyer, H. H., and Rapoport, T. A. (2001) The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414, 652–656.PubMedCrossRefGoogle Scholar
  29. 29.
    Wu, Y., Whitman, I., Molmenti, E., Moore, K., Hippenmeyer, P., and Perlmutter, D. H. (1994) A lag in intracellular degradation of mutant α1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ α1-antitrypsin deficiency. Proc. Natl. Acad. Sci. USA 91, 9014–9018.PubMedCrossRefGoogle Scholar
  30. 30.
    Kisen, G. O., Tessitore, L., Costelli, P., Gordon, P. B., Schwarze, P. E., Baccino, F. M., and Seglen, P. O. (1993) Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells. Carcinogenesis 14, 2501–2505.PubMedCrossRefGoogle Scholar
  31. 31.
    Liang, X. H., Jackson, S., Seaman, M., Brown, K., Kempkes, B., Hibshoosh, H., and Levine, B. (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676.PubMedCrossRefGoogle Scholar
  32. 32.
    Geller, S. A., Nichols, W. S., Kim, S., Tolmachoff, T., Lee, S., Dycaico, M. J., Felts, K., and Sorge, J. A. (1994) Hepatocarcinogenesis is the sequel to hepatitis in Z #2 alpha-1-antitrypsin transgenic mice: histopathological and DNA ploidy studies. Hepatology 9, 389–397.CrossRefGoogle Scholar
  33. 33.
    Johnston, J. A., Ward, C. L., and Kopito, R. R. (1998) Aggresomes: a cellular response to misfolded proteins. J. Cell. Biol. 7, 1883–1898.CrossRefGoogle Scholar
  34. 34.
    Kopito, R. R. (2000) Aggresomes, inclusion bodies and protein aggression. Trends Cell. Biol. 10, 524–527.PubMedCrossRefGoogle Scholar
  35. 35.
    Kopito, R. R. and Sitia, R. (2000) Aggresomes and Russell bodies. Symptoms of cellular indigestion? EMBO J. 3, 225–231.Google Scholar
  36. 36.
    Teckman, J. H., An, J.-K., Loethen, S., and Perlmutter, D. H. Fasting in α1-antitrypsin deficient liver: constitutive activation of autophagy. Am. J. Physiol. (2000) 283:G1156–G1165.Google Scholar
  37. 37.
    Nishino, I., Fu, J., Tanji, K., Yamada, T., Shimojo, S., Koori, T., et al. (2000) Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406, 906–910.PubMedCrossRefGoogle Scholar
  38. 38.
    Tanka, Y., Guhde, G., Suter, A., Eskelinen, E.-L., Hartmann, D., Lullmann-Rauch, R., et al. (2000) Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406, 902–906.CrossRefGoogle Scholar
  39. 39.
    Teckman, J. H., An, J.-K., Loethen, S., and Perlmutter, D. H. Mitochondrial autophagy and injury in the liver in alpha-1antitrypsin deficiency. J. Clin. Invest. (in review).Google Scholar
  40. 40.
    Lemasters, J. J., Nieminen, A. L., Qian, T., Trost, L. C., Elmore, S. P., Nishimura, Y., et al. (1998) The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim. Biophys. Acta 1366, 177–196.PubMedCrossRefGoogle Scholar
  41. 41.
    Elmore, S. P., Qian T., Grissom, D. F., and Lemasters, J. J. (2001) The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J. 15, 2286–2287.PubMedGoogle Scholar
  42. 42.
    Perkins, G., Renken, C., Martone, M. E., Young, S. J., Ellisman, M., and Frey, T. (1997) Electrom tomography of neuronal mitochondria: three-dimensional structure and organization of cristae and membrane contacts. J. Struct. Biol. 119, 260–272.PubMedCrossRefGoogle Scholar
  43. 43.
    Achleitner, G., Gaigg, B., Krasser, A., Kainersdorfer, E., Kohlwein, S. D., Perktold, A., et al. (1999) Association between the endoplasmic reticulum and mitochondria of yeast facilitates intraorganelle transport of phospholipids through membrane contact. Eur. J. Biochem. 264, 545–553.PubMedCrossRefGoogle Scholar
  44. 44.
    Wang, H.-J., Guay, G., Pogan, L., Sauve, R., and Nabi, I. R. (2000) Calcium regulates the association between mitochondria and a smooth subdomain of the endoplasmic reticulum. J. Cell. Biol. 150, 1489–1497.PubMedCrossRefGoogle Scholar
  45. 45.
    Arnaudeau, S., Kelley, W. L., Walsh, J. V., and Demaurex, N. (2001) Mitochondria recycle Ca2+ to the endoplasmic reticulum and prevent the depletion of neighboring endoplasmic reticulum regions. J. Biol. Chem. 276, 29,430–29,439.PubMedCrossRefGoogle Scholar
  46. 46.
    Hacki, J., Egger, L., Conus, S., Rosse, T., Fellay, I., and Borner, C. (2000) Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19, 2286–2295.PubMedCrossRefGoogle Scholar
  47. 47.
    Wei, M. C., Zong, W.-X., Cheng, E. H.-Y., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., et al. (2001) Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730.PubMedCrossRefGoogle Scholar
  48. 48.
    Sato, S, Ward C. L., Krouse, M. E., Wine J. J., and Kopito, R. R. (1996) Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J. Biol. Chem. 271, 635–638.PubMedCrossRefGoogle Scholar
  49. 49.
    Tamarappoo, B. and Verkman, A. S. (1998) Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J. Clin. Invest. 101, 2257–2267.PubMedCrossRefGoogle Scholar
  50. 50.
    Brown, C. R., Hong-Brown, L. Q., and Welch, W. J. (1997) Correcting temperature-sensitive protein folding defects. J. Clin. Invest. 101, 2257–2267.Google Scholar
  51. 51.
    Campbell, E. J., Campbell, M. A., Boudedes, S. S., and Owens, C. A. (1999) Quantum proteolysis by neutrophils: implications for pulmonary emphysema in α1-antitrypsin deficiency. J. Clin. Invest. 99, 1432–1444.Google Scholar
  52. 52.
    Jacob G. S. (1995) Gycosylation inhibitors in biology and medicine. Curr. Opin. Struc. Biol. 5, 605–611.CrossRefGoogle Scholar
  53. 53.
    Zitzmann, N., Mehta, A.S., Carrouee, S., Butters, T.D., Platt, F.J., McCauley, J., et al. (1999) Imino sugars inhibit the formation and secfretion of bovine viral diarrhea virus, a pestvirus model of hepatitis C virus: implications for the development of broad spectrum antihepatitis virus agents. Proc. Natl. Acad. Sci. USA 96, 11,878–11,882.PubMedCrossRefGoogle Scholar
  54. 54.
    Marcus, N. Y. and Perlmutter, D. H. (2000) Glucosidase and mannosidase inhibitors mediate increased secretion of mutant α1 antitrypsin Z. J. Biol. Chem. 275, 1987–1992.CrossRefGoogle Scholar
  55. 55.
    Novoradovskaya N., Lee J., Yu, Z. X., Ferrans, V. J., and Brantly, M. (1998) Inhibition of intracellular degradation increases secretion of a mutant for of α1-antitrypsin associated with profound deficiency. J. Clin. Invest. 1, 2693–2701.CrossRefGoogle Scholar
  56. 56.
    Rhim, J. A., Sandgen, E. P., Degen, J. L., Palmiter, R. D., and Brinster, R. L. (1994) Replacement of disease mouse liver by hepatic cell transplantation. Science 280, 1593–1596.Google Scholar
  57. 57.
    Overturf K, Al-Dhalimy M, Tanguay R, Brantly, M., Ou, C. N., Finegold, M., and Crompe, M. (1996) Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat. Genet. 12, 266–273.PubMedCrossRefGoogle Scholar
  58. 58.
    Mahadeva, R., Dafforn, T. R., Carrell, R. W., and Lomas, D. A. (2002) 6-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerizations: implications for the prevention of Z α1-antitrypsin-related cirrhosis. J. Biol. Chem. 277, 6771–6774.PubMedCrossRefGoogle Scholar
  59. 59.
    Day, P. M., Yewdell, J. W., Porgador A., Germain, R. N., and Bennink, J. R. (1997) Direct delivery of exogenous MHC class I molecule-binding oligopeptides to the endoplasmic reticulum of viable cells. Proc. Natl. Acad. Sci. USA 94, 8064–8069.PubMedCrossRefGoogle Scholar
  60. 60.
    Lord, J. M. and Roberts, L. M. (1998) Toxin entry: retrograde transport through the secretory pathway. J. Cell Biol. 140, 733–736.PubMedCrossRefGoogle Scholar
  61. 61.
    Carrell, R. W., Evans, D. L., and Stein, D. E. (1991) Mobile reactive centre of serpins and the control of thrombosis. Nature 353, 576–578.PubMedCrossRefGoogle Scholar
  62. 62.
    Elliott, P. R., Lomas, D. A., Carrell, R. W., and Abrahams, J. P. (1996) Inhibitory conformation of the reactive loop of α1-antitrypsin. Nature Struct. Biol. 2, 676–681.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2003

Authors and Affiliations

  • David H. Perlmutter
    • 1
    • 2
  1. 1.Department of PediatricsUniversity of Pittsburgh School of MedicinePittsburgh
  2. 2.Children’s Hospital of PittsburghPittsburgh

Personalised recommendations