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23 - α1-Antitrypsin Deficiency

from SECTION IV - METABOLIC LIVER DISEASE

Published online by Cambridge University Press:  18 December 2009

David H. Perlmutter M.D.
Affiliation:
Vira I. Heinz Professor and Chair, Department of Pediatrics, Professor of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Physician-in-Chief and Scientific Director, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Frederick J. Suchy
Affiliation:
Mount Sinai School of Medicine, New York
Ronald J. Sokol
Affiliation:
University of Colorado, Denver
William F. Balistreri
Affiliation:
University of Cincinnati
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Summary

Homozygous PIZZ α1-antitrypsin (α1-AT) deficiency is a relatively common genetic disorder, affecting 1 in 1600 to 1 in 2000 live births [1, 2]. It is an autosomal codominant disorder associated with 85–90% reduction in serum concentrations of α1-AT. A single amino acid substitution results in an abnormally folded protein that is unable to traverse the secretory pathway. The mutant α1-ATZ protein is retained in the endoplasmic reticulum (ER) rather than secreted into the blood and body fluids.

α1-Antitrypsin is an approximately 55-kDa secretory glycoprotein that inhibits destructive neutrophil proteases, elastase, cathepsin G, and proteinase 3. Plasma α1-AT is derived predominantly from the liver and increases three- to fivefold during the host response to tissue injury or inflammation. It is the archetype of a family of structurally related circulating serine protease inhibitors called serpins.

Nationwide prospective screening studies done by Sveger [1, 3] in Sweden have shown that only 8–10% of the PIZZ population develops clinically significant liver disease over the first 20 years of life. Nevertheless, this deficiency is the most frequent genetic cause of liver disease in children and the most frequent genetic disease for which children undergo orthotropic liver transplantation. It also has been associated with chronic hepatitis, cirrhosis, and hepatocellular carcinoma in adults [4].

Although the condition does not affect children, many α1-AT-deficient individuals develop destructive lung disease and emphysema.

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Publisher: Cambridge University Press
Print publication year: 2007

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References

Sveger, T. Liver disease in α-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976;294:1216–21.CrossRefGoogle Scholar
Silverman, E K, Miletich, J P, Pierce, J A. Alpha-1-antitrypsin deficiency: prevalence estimation from direct population screening. Am Rev Respir Dis 1989;140:961–6.CrossRefGoogle ScholarPubMed
Sveger, T. The natural history of liver disease in alpha-1-antitrypsin deficient children. Acta Paediatr Scand 1995;77:847–51.CrossRefGoogle Scholar
Eriksson, S, Carlson, J, Velez, R. Risk of cirrhosis and primary liver cancer in alpha-1-antitrypsin deficiency. N Engl J Med 1986;314:736–9.CrossRefGoogle ScholarPubMed
Gadek, J E, Fells, G A, Zimmerman, R L. Antielastases of the human alveolar structure: implications for the protease–antiprotease theory of emphysema. J Clin Invest 1981;68:889–98.CrossRefGoogle Scholar
Perlmutter, D H, Pierce, J A. The alpha-1-antitrypsin gene and emphysema. Am J Physiol 1989;257:L147–62.Google ScholarPubMed
Janoff, A. Elastases and emphysema: current assessment of the protease–antiprotease hypothesis. Am Rev Respir Dis 1985;132:417–33.Google ScholarPubMed
Crystal, R G. Alpha-1-antitrypsin deficiency, emphysema and liver disease: genetic basis and strategies for therapy. J Clin Invest 1990;95:1343–52.CrossRefGoogle Scholar
Carlson, J A, Rogers, B B, Sifers, R N. Accumulation of PiZ antitrypsin causes liver damage in transgenic mice. J Clin Invest 1988;83:1183–90.CrossRefGoogle Scholar
Dyaico, J M, Grant, S G N, Felts, K. Neonatal hepatitis induced by alpha-1-antitrypsin: a transgenic mouse model. Science 1988;242:1409–12.CrossRefGoogle Scholar
Sharp, H L, Bridges, R A, Krivit, W. Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder. J Lab Clin Med 1969;73:934–9.Google ScholarPubMed
Hope, P L, Hall, M A, Millward-Sadler, G H. Alpha-1-antitrypsin deficiency presenting as a bleeding diathesis in the newborn. Arch Dis Child 1982;57:68–70.Google ScholarPubMed
Ghishan, F R, Gray, G F, Greene, H L. α-antitrypsin deficiency presenting with ascites and cirrhosis in the neonatal period. Gastroenterology 1983;85:435–8.Google Scholar
Zhou, H, Fischer, H-P. Liver carcinoma in PiZ alpha-1-antitrypsin deficiency. Am J Surg Pathol 1998;22:742–8.CrossRefGoogle ScholarPubMed
Zhou, H, Ortiz-Pallardo, M E, Ko, Y, Fischer, H-P. Is heterozygous alpha-1-antitrypsin deficiency type PiZ a risk factor for primary liver carcinoma?Cancer 2000;88:2668–76.3.0.CO;2-G>CrossRefGoogle ScholarPubMed
Nebbia, G, Hadchouel, M, Odievre, M. Early assessment of evolution of liver disease associated with α-antitrypsin deficiency in childhood. J Pediatr 1983;102:661–5.CrossRefGoogle Scholar
Ibarguen, E, Gross, C R, Savik, S K, Sharp, H L. Liver disease in α-antitrypsin deficiency: prognostic indicators. J Pediatr 1990;117:864–70.CrossRefGoogle Scholar
Volpert, D, Molleston, J P, Perlmutter, D H. Alpha1-antitrypsin deficiency-associated liver disease progresses slowly in some children. J Pediatr Gastro Nutr 2000;31:258–63.CrossRefGoogle ScholarPubMed
Starzl, T E, Porter, K A, Busuttil, R W. Liver disease in alpha-1-antitrypsin deficiency: prognostic indicators. J Pediatr 1990;117:864–70.Google Scholar
Hodges, J R, Millward Sadler, G H, Barbatis, C. Heterozygous MZ α-antitrypsin deficiency in adults with chronic active hepatitis and cryptogenic cirrhosis. N Engl J Med 1981;304:357–60.CrossRefGoogle Scholar
Graziadei, I W, Joseph, J J, Wiesner, R H. Increased risk of chronic liver failure in adults with heterozygous α-antitrypsin deficiency. Hepatology 1998;28:1058–63.CrossRefGoogle Scholar
Propst, T, Propst, A, Dietze, O. High prevalence of viral infections in adults with homozygous and heterozygous α-antitrypsin deficiency and chronic liver disease. Ann Intern Med 1992;117:641–5.CrossRefGoogle Scholar
Reid, C L, Wiener, G J, Cox, D W. Diffuse hepatocellular dysplasia and carcinoma associated with the Mmalton variant of α-antitrypsin. Gastroenterology 1987;93:181–7.CrossRefGoogle Scholar
Curiel, D T, Holmes, M D, Okayama, H. Molecular basis of the liver and lung disease associated with α-antitrypsin deficiency allele Mmalton. J Biol Chem 1989;264:13938–45.Google Scholar
Lomas, D A, Elliott, P R, Sidhar, S K. α-antitrypsin Mmalton [Phe52] forms loop-sheet polymers in vivo: evidence for the C-sheet mechanism of polymerization. J Biol Chem 1995;270:16864–74.CrossRefGoogle Scholar
Mahadeva, R, Chang, W-SW, Dafforn, T R. Heteropolymerization of S, I, and Z α-antitrypsin and liver cirrhosis. J Clin Invest 1999;103:999–1006.CrossRefGoogle Scholar
Teckman, J H, Perlmutter, D H. The endoplasmic reticulum degradation pathway for mutant secretory proteins α-antitrypsin Z and S is distinct from that for an unassembled membrane protein. J Biol Chem 1996;271:13215–20.CrossRefGoogle Scholar
Crowley, J J, Sharp, H L, Freier, E. Fatal liver disease associated with α-antitrypsin deficiency PIM/PIMduarte. Gastroenterology 1987;93:242–4.CrossRefGoogle Scholar
Clark, P, Chong, A Y H. Rare alpha-1-antitrypsin allele PIW and a history of infant liver disease. Am J Med Genet 1992;45:674–6.CrossRefGoogle Scholar
Kelly, C P, Tyrrell, D N M, McDonald, G S A. Heterozygous FZ α-antitrypsin deficiency associated with severe emphysema and hepatic disease: case report and family study. Thorax 1989;44:758–9.CrossRefGoogle Scholar
Eriksson, S. Alpha-1-antitrypsin deficiency and liver cirrhosis in adults. Acta Med Scand 1987;221:461–7.CrossRefGoogle ScholarPubMed
Silverman, E K, Province, M A, Rao, D C. A family study of the variability of pulmonary function in alpha-1-antitrypsin deficiency. Am Rev Respir Dis 1990;142:1015–21.CrossRefGoogle ScholarPubMed
Guenter, C A, Welch, M H, Russell, T R. The pattern of lung disease associated with alpha-1-antitrypsin deficiency. Arch Intern Med 1968;122:254–9.CrossRefGoogle Scholar
Thurlbeck, W M, Henderson, J A, Fraser, R G. Chronic obstructive disease: a comparison between clinical, roentgenologic, functional and morphologic criteria in chronic bronchitis, emphysema, asthma and bronchiectasis. Medicine 1970;49:81–98.CrossRefGoogle Scholar
Glasgow, J F T, Lynch, M J, Hercz, A. Alpha1 antitrypsin deficiency in association with both cirrhosis and chronic obstructive lung disease in two sibs. Am J Med 1973;54:181–94.CrossRefGoogle Scholar
Talamo, R C, Levison, H, Lynch, M J. Symptomatic pulmonary emphysema in childhood associated with hereditary alpha-1-antitrypsin and elastase inhibitor deficiency. J Pediatr 1971;79:20–6.CrossRefGoogle ScholarPubMed
Houstek, J, Copova, M, Zapletal, A. Alpha1-antitrypsin deficiency in a child with chronic lung disease. Chest 1973;64:773–6.CrossRefGoogle Scholar
Dunand, P, Cropp, G A, Middleton, E. Severe obstructive lung disease in a 14-year-old girl with alpha-1 antitrypsin deficiency. J Allergy Clin Immunol 1975;57:615–22.CrossRefGoogle Scholar
Wagener, J S, Sobonya, R E, Taussig, L M. Unusual abnormalities in adolescent siblings with α-antitrypsin deficiency. Chest 1983;83:464–8.CrossRefGoogle Scholar
Hird, M F, Greenough, A, Mieli-Vergani, G. Hyperinflation in children with liver disease due to α-antitrypsin deficiency. Pediatr Pulmonol 1991;11:212–16.CrossRefGoogle Scholar
Wiebicke, W, Niggermann, B, Fischer, A. Pulmonary function in children with homozygous alpha-1-protease inhibitory deficiency. Eur J Pediatr 1996;155:603–7.Google Scholar
Larsson, C. Natural history and life expectancy in severe alpha-1-antitryspin deficiency, PiZ. Acta Med Scand 1978;204:345–51.CrossRefGoogle Scholar
Janus, E D, Phillips, N T, Carrell, R W. Smoking, lung function and alpha-1-antitrypsin deficiency. Lancet 1985;I:152–4.CrossRefGoogle Scholar
Schonfeld, J V, Brewer, N, Zotz,, R. Liver function in patients with pulmonary emphysema due to severe alpha-1-antitrypsin deficiency (PIZZ). Digestion 1996;57:165–9.CrossRefGoogle Scholar
Huber, R, Carrell, R W. Implications of the three-dimensional structure of alpha-1-antitrypsin for structure and function of serpins. Biochemistry 1990;28:8951–66.CrossRefGoogle Scholar
Vaughan, L, Lorier, M A, Carrell, R W. Alpha-1-antitrypsin microheterogeneity: isolation and physiological significance of isoforms. Biochim Biophys Acta 1982;701:339–45.CrossRefGoogle ScholarPubMed
Silverman, G A, Bird, P I, Carrell, R W. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions and a revised nomenclature. J Biol Chem 2000;276:33293–6.CrossRefGoogle Scholar
Elliott, P R, Lomas, D A, Carrell, R W. Inhibitory conformation of the reactive loop of α-antitrypsin. Nat Struct Biol 1996;3:676–81.CrossRefGoogle Scholar
Elliott, P R, Abrahams, J-P, Lomas, D A. Wild-type α-antitrypsin is in the cannonical inhibitory conformation. J Mol Biol 1998;275:419–25.CrossRefGoogle Scholar
Owen, M C, Brennan, S O, Lewis, J H. Mutation of anti-trypsin to antithrombin: alpha-1-antitrypsin Pittsburgh (358 Met-Arg), a fatal bleeding disorder. N Engl J Med 1983;309:694–8.CrossRefGoogle Scholar
Banda, M J, Rice, A G, Griffin, G L. Alpha-1-proteinase inhibitor is a neutrophil chemoattractant after proteolytic inactivation by macrophage elastase. J Biol Chem 1988;263:4481–4.Google ScholarPubMed
Banda, M J, Rice, A G, Griffin, G L. The inhibitory complex of human alpha-1-proteinase inhibitor and human leukocyte elastase is a neutrophil chemoattractant. J Exp Med 1988;167:1608–15.CrossRefGoogle ScholarPubMed
Perlmutter, D H, Glover, G I, Rivetna, M. Identification of a serpin-enzyme complex (SEC) receptor on human hepatoma cells and human monocytes. Proc Natl Acad Sci U S A 1990;87:3753–7.CrossRefGoogle ScholarPubMed
Perlmutter, D H, Joslin, G, Nelson, P. Endocytosis and degradation of alpha-1-antitrypsin-proteinase complexes is mediated by the SEC receptor. J Biol Chem 1990;265:16713–16.Google ScholarPubMed
Long, G L, Chandra, T, Woo, S L C. Complete nucleotide sequence of the cDNA for human alpha-1-antitrypsin and the gene for the S variant. Biochemistry 1984;23:4828–37.CrossRefGoogle ScholarPubMed
Lai, E C, Kao, F-F, Law, M L. Assignment of the alpha-1-antitrypsin gene and sequence-related gene to human chromosome 14 by molecular hybridization. Am J Hum Genet 1983;35:385–92.Google ScholarPubMed
Pearson, S J, Tetri, P, George, D L. Activation of human alpha-1-antitrypsin gene in rat hepatoma x human fetal liver cell hybrids depends on presence of human chromosome 14. Somat Cell Mol Genet 1983;9:567–92.CrossRefGoogle ScholarPubMed
Rabin, M, Watson, M, Kidd, V. Activation of human alpha-1-antichymotrypsin and alpha-1-antitrypsin genes on human chromosome 14. Somat Cell Mol Genet 1986;12:209–14.CrossRefGoogle Scholar
Perlino, E, Cortese, R, Ciliberto, G. The human alpha-1-antitrypsin gene is transcribed from two different promoters in macrophages and hepatocytes. EMBO J 1987;6:2767–71.Google ScholarPubMed
Hofker, M H, Nelen, M, Klasen, E C. Cloning and characterization of an alpha-1-antitrypsin-like gene 12 kb downstream of the genuine alpha-1-antitrypsin gene. Biochem Biophys Res Comm 1988;155:634–42.CrossRefGoogle Scholar
Kelsey, G D, Parker, M, Povey, S. The human alpha-1-antitrypsin-related sequence gene: isolation and investigation of its sequence. Ann Hum Genet 1988:52:151–60.CrossRefGoogle Scholar
Sefton, L, Kelsey, G, KearneyP, et al P, et al. A physical map of human PI and AACT genes. Genomics 1990;7:382–8.CrossRefGoogle ScholarPubMed
Seralini, G-E, Berube, D, Gagne, R. The human corticosteroid binding globulin gene is located on chromosome 14q31-q32.1 near two other serine protease inhibitor genes. Hum Genet 1990;80:75–8.Google Scholar
Hafeez, W, Ciliberto, G, Perlmutter, D H. Constitutive and modulated expression of the human alpha-1-antitrypsin gene: different transcriptional initiation sites used in three different cell types. J Clin Invest 1992;89:1214–22.CrossRefGoogle ScholarPubMed
Pierce, J A, Erdio, B G. Improved identification of antitrypsin phenotypes through isoelectric focusing with dithioerythritol. J Lab Clin Med 1979;94:826–31.Google ScholarPubMed
Barker, A, Brantly, M, Campbell, E. α-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ 1997;75:397–415.Google Scholar
Nukiwa, T, Brantly, M L, Ogushi, F. Characterization of the M1 (ala 213) type of alpha-1-antitrypsin haplotype. Biochemistry 1987;26:5259–67.CrossRefGoogle ScholarPubMed
Dykes, D, Miller, S, Polesky, H. Distribution of alpha-1-antitrypsin variants in a U.S. white population. Hum Hered 1984;34:308–10.CrossRefGoogle Scholar
Kueppers, F, Christopherson, M J. alpha-1-antitrypsin: further genetic heterogeneity revealed by isoelectric focusing. Am J Hum Genet 1978;85:381–2.Google Scholar
Graham, A, Hayes, K, Weidinger, S. Characterization of alpha-1-antitrypsin M3 gene, a normal variant. Hum Genet 1990;85:381–2.CrossRefGoogle Scholar
Jeppsson, J-O, Laurell, C-B. The amino acid substitutions of human alpha-1-antitrypsin M3, X and Z. FEBS Lett 1988;231:327–30.CrossRefGoogle ScholarPubMed
Brennan, S O, Carrell, R W. alpha-1-antitrypsin Christchurch, 363Glu-Lys: mutation at the P′5 position does not affect inhibitory activity. Biochim Biophys Acta 1986;573:13–19.CrossRefGoogle Scholar
Holmes, M D, Brantly, M L, Crystal, R G. Molecular analysis of the heterogeneity among the P-family of alpha-1-antitrypsin alleles. Am Rev Respir Dis 1990;142:1185–92.CrossRefGoogle ScholarPubMed
Talamo, R C, Langley, C E, Reed, C E. alpha-1-antitrypsin deficiency: a variant with no detectable alpha-1-antitrypsin. Science 1973;181:70–1.CrossRefGoogle Scholar
Takahashi, H, Crystal, R G. Alpha-1-antitrypsin null isola di procida: alpha-1-antitrypsin deficiency allele caused by deletion of all alpha-1-antitrypsin coding exons. Am J Hum Genet 1990;47:403–13.Google ScholarPubMed
Poller, W, Faber, J-P, Neidinger, S. DNA polymorphisms associated with a new alpha-1-antitrypsin PIQO variant (PIQO reidenberg). Hum Genet 1991;86:522–4.CrossRefGoogle Scholar
Garver, R I, Mornex, J-P, Nukiwa, T. Alpha-1-antitrypsin deficiency and emphysema caused by homozygous inheritance of on-expressing alpha-1-antitrypsin genes. N Engl J Med 1986;314:762–6.CrossRefGoogle Scholar
Satoh, K, Nukiwa, T, Brantly, M. Emphysema associated with complete absence of alpha-1-antitrypsin in serum and the homozygous inheritance of stop codon in an alpha-1-antitrypsin coding exon. Am J Hum Genet 1988;42:77–83.Google Scholar
Holmes, M, Curiel, D, Brantly, M. Characterization of the intracellular mechanism causing the alpha-1-antitrypsin Nullgranite falls deficiency state. Am Rev Respir Dis 1989;140:1662–7.CrossRefGoogle ScholarPubMed
Nukiwa, T, Takahashi, H, Brantly, M. Alpha-1-antitrypsin Nullgranite Falls>: a nonexpressing alpha-1-antitrypsin gene associated with a frameshift stop mutation in a coding exon. J Biol Chem 1987;262:11999–2004.Google Scholar
Curiel, D, Brantly, M, Curiel, E. Alpha-1-antitrypsin deficiency caused by the alpha-1-antitryspin null mattawa gene: an insertion mutation rendering the alpha-1-antitrypsin gene incapable of producing alpha-1-antitrypsin. J Clin Invest 1989;83:1144–52.CrossRefGoogle Scholar
Muensch, H, Gaidulis, L, Kueppers, F. Complete absence of serum alpha-1-antitrypsin in conjunction with an apparently normal gene structure. Am J Hum Genet 1986;38:898–907.Google ScholarPubMed
Sifers, R N, Brashears-Macatee, S, Kidd, V J. A frameshift mutation results in a truncated alpha-1-antitrypsin that is retained within the rough endoplasmic reticulum. J Biol Chem 1988;263:7330–5.Google Scholar
Brantly, M, Lee, J H, Hildeshiem, J. α-antitrypsin gene mutation hot spot associated with the formation of a retained and degraded null variant. Am J Respir Cell Mol Biol 1997;16:224–31.CrossRefGoogle Scholar
Carrell, R W. Alpha-1-antitrypsin molecular pathology, leukocytes and tissue damage. J Clin Invest 1986;77:1427–31.CrossRefGoogle Scholar
Curiel, D, Chytil, A, Courtney, M. Serum alpha-1-antitrypsin deficiency associated with the common S-type (Glu364-Val) mutation results in intracellular degradation of alpha-1-antitrypsin prior to secretion. J Biol Chem 1989;264:10477–86.Google Scholar
Hofker, M H, Nukiwa, T, Paassen, H M B. A Pro-Leu substitution in codon 369 in the alpha-1-antitrypsin deficiency variant PiMheerlen. Am J Hum Genet 1987;41:A220[abstract].Google Scholar
Takahashi, H, Nukiwa, T, Satoh, K. Characterization of the gene and protein of the alpha-1-antitrypsin “deficiency” allele M procida. J Biol Chem 1988;263:15528–34.Google Scholar
Sproule, B J, Cox, S W, Hsu, K. Pulmonary function associated with the M malton deficient variant of alpha-1-antitrypsin. Am Rev Respir Dis 1983;127:237–40.Google Scholar
Curiel, D T, Vogelmeier, C, Hubbard, R C. Molecular basis of alpha-1-antitrypsin deficiency and emphysema associated with alpha-1-antitrypsin M mineral springs allele. Mol Cell Biol 1990;10:47–56.CrossRefGoogle Scholar
Holmes, M D, Brantley, M L, Fells, G A. Alpha-1-antitrypsin WBethesda: molecular basis of an unusual alpha-1-antitrypsin deficiency variant. Biochem Biophys Res Comm 1990;170:1013–22.CrossRefGoogle ScholarPubMed
Seyama, K, Nukiwa, T, Takabe, K. Siiyama serine 53 [TCC] to phenylalanine 53 (TTC): a new alpha-1-antitrypsin deficient variant with mutation on a predicted conserved residue of the serpin backbone. J Biol Chem 1991;266:12627–32.Google ScholarPubMed
Okayama, H, Brantly, M, Holmes, M. Characterization of the molecular basis of the alpha-1-antitrypsin F allele. Am J Hum Genet 1991;47:1154–8.Google Scholar
Graham, A, Kalsheker, N A, Bamforth, F J. Molecular characterization of two alpha-1-antitrypsin deficiency variants: proteinase inhibitor (Pi) Null newport (Gly165-Ser) and (Pi) Z Wrexham (Ser-19-Leu). Hum Genet 1990;85:537–40.CrossRefGoogle Scholar
Senior, R M, Tegner, H, Kuhn, C. The induction of pulmonary emphysema with human leukocyte elastase. Am Rev Respir Dis 1977;116:469–75.CrossRefGoogle ScholarPubMed
Travis, J, Salvesen, G S. Human plasma proteinase inhibitors. Annu Rev Biochem 1983;52:655–709.CrossRefGoogle ScholarPubMed
Carp, H, Janoff, A. Possible mechanisms of emphysema in smokers: in vitro suppression of serum elastase inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis 1978;118:617–21.Google ScholarPubMed
Ossanna, P J, Test, S, Matheson, N R. Oxidative regulation and neutrophil elastase-alpha-1-proteinase inhibitor interactions. J Clin Invest 1986;72:1939–51.CrossRefGoogle Scholar
Hubbard, R C, Ogushi, F, Fells, G A. Oxidants spontaneously released by alveolar macrophages of cigarette smokers can inactivate the active site of α-antitrypsin, rendering it ineffective as an inhibitor of neutrophil elastase. J Clin Invest 1987;80:1289–95.CrossRefGoogle Scholar
Mast, A E, Enghild, J, Nagase, H. Kinetics and physiologic relevance of the inactivation of α-proteinase inhibitor, α-antichymotrypsin, and antithrombin III by matrix metalloproteinases-1 (tissue collagenase), -1 (72-kDa gelatinase/type IV collagenase), and -3 (stromelysin). J Biol Chem 1991;266:15810–16.Google Scholar
Bathurst, I C, Travis, J, George, P M. Structural and functional characterization of the abnormal Z α-antitrypsin isolated from human liver. FEBS Lett 1984;177:179–83.CrossRefGoogle Scholar
Ogushi, F, Fells, G A, Hubbard, R C. Z-type α-antitrypsin is less competent than M1-type α-antitrypsin as an inhibitor of neutrophil elastase. J Clin Invest 1987;89:1366–74.CrossRefGoogle Scholar
Libert, C, Molle, W, Brouckaert, P. α-antitrypsin inhibits the lethal response to TNF in mice. J Immunol 1996;157:5126–9.Google Scholar
Molle, W, Libert, C, Fiers, W. α-acid glycoprotein and α-antitrypsin inhibit TNF-induced, but not anti-Fas-induced apoptosis of hepatocytes in mice. J Immunol 1997;159:3555–64.Google Scholar
Camussi, G, Tetta, C, Bussolino, F. Synthesis and release of platelet-activating factor is inhibited by plasma α-proteinase inhibitor or α-antichymotrypsin and is stimulated by proteinases. J Exp Med 1988;168:1293–306.CrossRefGoogle Scholar
Joslin, G, Griffin, G L I, August, A M. The serpin-enzyme complex [SEC] receptor mediate the neutrophil chemotactic effect of α-antitrypsin-elastse complexes and amyloid-β peptide. J Clin Invest 1992;90:1150–4.CrossRefGoogle ScholarPubMed
Wilson-Cox D. Alpha-1-antitrypsin deficiency. In: Scriber, C B, Beaudet, A L, Aly, Q A. The metabolic basis of inherited disease. New York: McGraw-Hill, 1989:2409–37.Google Scholar
Breit, S N, Wakefield, D, Robinson, J P. The role of alpha-1-antitrypsin deficiency in the pathogenesis of immune disorders. Clin Immun Immunopathol 1985;35:363–80.CrossRefGoogle ScholarPubMed
Hood, J M, Koep, L J, Peters, R L. Liver transplantation for advanced liver disease with α-antitrypsin deficiency. N Engl J Med 1980;302:272–6.CrossRefGoogle Scholar
Lodish, H F, Kong, N. Glucose removal from N-linked oligosaccharides is required for efficient maturation of certain secretory glycoproteins from the rough endoplasmic reticulum to the Golgi complex. J Cell Biol 1987;104:221–30.CrossRefGoogle Scholar
Liu, M-C, Yu, S, Sy, J. Tyrosine sulfation of proteins from human hepatoma cell line HepG2. Proc Natl Acad Sci U S A 1985;82:7160–4.CrossRefGoogle ScholarPubMed
DeSimone, V, Cortese, R. Transcription factors and liver-specific genes. J Biol Biophys Acta 1992;1132:119–26.Google Scholar
Tripodi, M, Abbott, C, Vivian, M. Disruption of the LF-A1 and LF-B1, binding sites in the human alpha-1-antitrypsin gene, has a differential effect during development in transgenic mice. EMBO J 1991;10:3177–82.Google Scholar
Hu, C, Perlmutter, D H. Regulation of α-antitrypsin gene expression in human intestinal epithelial cell line Caco2 by HNF1α and HNF4. Am J Physiol 1999;276:G1181–94.Google Scholar
Dickson, I, Alper, C A. Changes in serum proteinase inhibitor levels following bone surgery. Clin Chim Acta 1974;54:381–5.CrossRefGoogle ScholarPubMed
Perlmutter, D H, May, L T, Sehgal, P B. Interferon β2interleukin-6 modulates synthesis of α-antitrypsin in human mononuclear phagocytes and in human hepatoma cells. J Clin Invest 1989;264:9485–90.Google Scholar
Laurell, C-B, Rannevik, G. A comparison of plasma protein changes induced by danazol, pregnancy and estrogens. J Clin Endocrinol Metab 1979;49:719–25.CrossRefGoogle ScholarPubMed
Perlmutter, D H, Cole, F S, Kilbridge, P. Expression of the α-proteinase inhibitor gene in human monocytes and macrophages. Proc Natl Acad Sci U S A 1985;82:795–9.CrossRefGoogle Scholar
Barbey-Morel, C, Pierce, J A, Campbell, E J. Lipopolysaccharide modulates the expression of α-proteinase inhibitor and other serine proteinase inhibitors in human monocytes and macrophages. J Exp Med 1987;166:1041–54.CrossRefGoogle Scholar
Perlmutter, D H, Travis, J, Punsal, P I. Elastase regulates the synthesis of its inhibitors, α-proteinase inhibitor, and exaggerates the defect in homozygous PIZZ α-proteinase inhibitor deficiency. J Clin Invest 1988;81:1774–8.CrossRefGoogle Scholar
Joslin, G, Fallon, R J, Bullock, J. The SEC receptor recognizes a pentapeptide neo-domain of α-antitrypsin-protease complexes. J Biol Chem 1991;266:11281–8.Google Scholar
Joslin, G, Wittwer, A, Adams, S. Cross-competition for binding of α-antitrypsin (α-1-AT)-elastase complexes to the serpin-enzyme complex receptor by other serpin-enzyme complexes and by proteolytically modified α-1-AT. J Biol Chem 1993;268:1886–93.Google Scholar
Joslin, G, Krause, J E, Hershey, E D. Amyloid-β peptide, substance P and bombesin bind to the serpin-enzyme complex receptor. J Biol Chem 1991;266:21897–902.Google ScholarPubMed
Boland, K, Behrens, M, Choi, D. The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-β peptide but not aggregated, cytotoxic amyloid-β peptide. J Biol Chem 1996;271:18032–44.CrossRefGoogle Scholar
Mast, A E, Enghild, J J, Pizzo, S V. Analysis of plasma elimination kinetics and conformation stabilities of native, proteinase-complexed and reactive site cleaved serpins: comparison of α-proteinase inhibitor, α-antichymotrypsin, antithrombin III, α2-antiplasmin, angiotensinogen, and ovalbumin. Biochemistry 1991;30:1723–30.CrossRefGoogle Scholar
Poller, W, Willnow, T E, Hilpert, J. Differential recognition of α-antitrypsin-elastase and α-antichymotrypsin-cathespin G complexes by the low density lipoprotein receptor-related protein. J Biol Chem 1995;270:2841–5.CrossRefGoogle Scholar
Kounnas, M Z, Church, F C, Argraves, W S. Cellular internalization and degradation of antithrombin-III-thrombin, heparin cofactor II-thrombin, and α-antitrypsin-trypsin complexes is mediated by the low density lipoprotein receptor-related protein. J Biol Chem 1996;271:6523–9.CrossRefGoogle ScholarPubMed
Kelsey, G D, Povey, S, Bygrave, A E. Species-and tissue-specific expression of human alpha-1-antitrypsin in transgenic mice. Genes Dev 1987;1:161–70.CrossRefGoogle ScholarPubMed
Koopman, P, Povey, S, Lovel-Badge, R H. Widespread expression of human alpha-1-antitrypsin in transgenic mice revealed by in situ hybridization. Genes Dev 1989;3:16–25.CrossRefGoogle ScholarPubMed
Carlson, J A, Rogers, B B, Sifers, R N. Multiple tissues express alpha-1-antitrypsin in transgenic mice and man. J Clin Invest 1988;82:26–36.CrossRefGoogle ScholarPubMed
Molmenti, E P, Perlmutter, D H, Rubin, D C. Cell-specific expression of α-antitrypsin in human intestinal epithelium. J Clin Invest 1993;92:2022–34.CrossRefGoogle Scholar
Venembre, P, Boutten, A, Seta, N. Secretion of α-antitryupsin by alveolar epithelial cells. FEBS Lett 1994;346:171–4.Google ScholarPubMed
Cichy, J, Potempa, J, Travis, J. Biosynthesis of α-proteinase inhibitor by human lung-derived epithelial cells. J Biol Chem 1997;272:8250–5.CrossRefGoogle Scholar
Makino, S, Reed, C E. Distribution and elimination of exogenous alpha-1-antitrypsin. J Lab Clin Med 1977;52:457–61.Google Scholar
Laurell, C-B, Nosslin, B, Jeppsson, J-O. Catabolic rate of α-antitrypsin of P1 type M and Z in man. Clin Sci Mol Med 1977;52:457–61.Google Scholar
Thomas, D W, Sinatra, F R, Merritt, R J. Random fecal alpha-1-antitrypsin concentration in children with gastrointestinal disease. Gastroenterology 1981;80:776–82.Google ScholarPubMed
Grill, B, Tinghitella, T, Hillemeier, C. Increased intestinal clearance of alpha-1-antitrypsin in patient with alpha-1-antitrypsin deficiency. J Pediatr Gastroenterol Nutr 1983;2:95–8.CrossRefGoogle ScholarPubMed
Kidd, V J, Walker, R B, Itakura, K. α-antitryupsin deficiency detection by direct analysis of the mutation of the gene. Nature (London) 1983;304:230–4.CrossRefGoogle ScholarPubMed
Jeppsson, J-O. Amino acid substitution Glu-Lys in α-antitrypsin PiZ. FEBS Lett 1976;65:195–7.CrossRefGoogle Scholar
Owen, M C, Carrell, R W. α-antitrypsin: sequence of the Z variant tryptic peptide. FEBS Lett 1976;79:247–9.Google Scholar
Perlmutter, D H, Kay, R M, Cole, F S. The cellular defect in α-proteinase inhibitor deficiency is expressed in human monocytes and xenopus oocytes injected with human liver mRNA. Proc Natl Acad Sci U S A 1985;82:6918–21.CrossRefGoogle Scholar
Foreman, R C, Judah, J D, Colman, A. Xenopus oocytes can synthesize but do not secrete the Z variant of human α-antitrypsin. FEBS Lett 1984;169:84–8.CrossRefGoogle Scholar
McCracken, A A, Kruse, K B, Brown, J L. Molecular basis for defective secretion of variants having altered potential for salt bridge formation between amino acids 240 and 242. Mol Cell Biol 1989;9:1408–14.CrossRefGoogle Scholar
Sifers, R N, Hardick, C P, Woo, S L C. Disruption of the 240–342 salt bridge is not responsible for the defect of the PIZ α-antitrypsin variant. J Biol Chem 1989;264:2997–3001.Google Scholar
Wu, Y, Foreman, R C. The effect of amino acid substitutions at position 342 on the secretion of human α-antitrypsin from xenopus oocytes. FEBS Lett 1990;268:21–3.CrossRefGoogle Scholar
Lomas, D A, Evans, D L, Finch, J J. The mechanism of Z α-antitrypsin accumulation in the liver. Nature 1992;357:605–7.CrossRefGoogle Scholar
Lomas, D A, Finch, J T, Seyama, K. α-antitrypsin Siiyama (SER53→Phe): further evidence for intracellular loop-sheet polymerization. J Biol Chem 1993;268:15333–5.Google Scholar
Elliott, P R, Stein, P E, Bilton, D. Structural explanation for the deficiency of S α-antitrypsin. Nature Struct Biol 1996;3:910–11.CrossRefGoogle Scholar
Sidhar, S K, Lomas, D A, Carrell, R W. Mutations which impede loop-sheet polymerization enhance the secretion of human α-antitrypsin deficiency variants. J Biol Chem 1995;270:8393–6.CrossRefGoogle Scholar
Kang, H A, Lee, K N, Yu, M-H. Folding and stability of the Z and Siiyama genetic variants of human α-antitrypsin. J Biol Chem 1997;272:510–16.CrossRefGoogle Scholar
Lin, L, Schmidt, B, Teckman, J, Perlmutter, D H. A naturally occurring non-polymerogenic mutant of α-antitrypsin characterized by prolonged retention in the endoplasmic reticulum. J Biol Chem 2001;276:33893–8.CrossRefGoogle Scholar
Schmidt, B Z, Perlmutter, D H. GRP78, GRP94 and GRP170 interact with α1 AT mutants that are retained in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol 2005;289:G444–55.CrossRefGoogle ScholarPubMed
Davis, R L, Shrimpton, A E, Holohan, P D. Familial dementia caused by polymerization of mutant neuroserpin. Nature 1999;401:376–9.CrossRefGoogle ScholarPubMed
Kamimoto, T, Shoji, S, Mizushima, N. Intracellular inclusions containing mutant α1 ATZ are propagated in the absence of autophagy. J Biol Chem 2006;281:4467–76CrossRefGoogle Scholar
Kruse, K B, Brodsky, J L, McCracken, A A. Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble α1 PiZ and another for aggregates of α1 PiZ. Mol Biol Cell 2006;17:203–12. Epub 2005 Nov 2.CrossRefGoogle Scholar
Hidvegi, T, Schmidt, B Z, Hale, P, Perlmutter, D H. Accumulation of mutant α-antitrypsin Z in the ER activates caspases-4 and -12, NFκB and BAP31 but not the unfolded protein response. J Biol Chem 2005;280:39002–15. Epub 2005 Sep 23.CrossRefGoogle Scholar
Wu, Y, Whitman, I, Molmenti, E. A lag in intracellular degradation of mutant α-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ α-antitrypsin deficiency. Proc Natl Acad Sci U S A 1994;91:9014–18.CrossRefGoogle Scholar
Werner, E D, Brodsky, J L, McCracken, A A. Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate. Proc Natl Acad Sci U S A 1996;93:13797–801.CrossRefGoogle ScholarPubMed
Qu, D, Teckman, J H, Omura, S, Perlmutter, D H. Degradation of mutant secretory protein, α-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J Biol Chem 1996;271:22791–5.CrossRefGoogle Scholar
Teckman, J H, Gilmore, R, Perlmutter, D H. Role of ubiquitin in proteasomal degradation of mutant α-antitrypsin Z in the endoplasmic reticulum. Am J Physiol 2000;278:G39–48.Google Scholar
Teckman, J H, Burrows, J, Hidvegi, T. The proteasome participants in degradation of mutant α-antitrypsin Z in the endoplasmic reticulum of hepatoma-derived hepatocytes. J Biol Chem 2001;276:44865–72.CrossRefGoogle Scholar
Cabral, C M, Liu, Y, Moremen, K W, Sifers, R N. Organizational diversity among distinct glycoprotein endoplasmic reticulum-associated degradation programs. Mol Biol Cell 2002;13:2639–50.CrossRefGoogle ScholarPubMed
Mayer, T, Braun, T, Jentsch, S. Role of the proteasome in membrane extraction of a short-lived ER-transmembrane protein. EMBO J 1998;17:3251–7.CrossRefGoogle ScholarPubMed
Cabral, C M, Choudhury, P, Liu, Y, Sifers, R N. Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways. J Biol Chem 2000;275:25015–22.CrossRefGoogle ScholarPubMed
Teckman, J H, Perlmutter, D H. Retention of mutant α-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol 2000;279:G961–74.Google Scholar
Teckman, J H, An, J K, Blomenkamp, K. Mitochondrial autophagy and injury in the liver in α-antitrypsin deficiency. Am J Physiol 2004;286:G851–62.Google Scholar
Perkins, G, Renken, C, Martone, M E. Electron tomography of neuronal mitochondria: three-dimensional structure and organization of cristae and membrane contacts. J Struct Biol 1997;119:260–72.CrossRefGoogle ScholarPubMed
Achleitner, G, Gaigg, B, Krasser, A. Association between the endoplasmic reticulum and mitochondria of yeast facilitates intraorganelle transport of phospholipids through membrane contact. Eur J Biochem 1999;264:545–53.CrossRefGoogle Scholar
Mizushima, N, Yamamoto, A, Matsui, M. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004;15:1101–11.CrossRefGoogle ScholarPubMed
Zhang, K, Kaufman, R J. Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem 2004;279:25935–8.CrossRefGoogle ScholarPubMed
Ron, D. Translational control in the endoplasmic reticulum stress response. J Clin Invest 2002;110:1383–8.CrossRefGoogle ScholarPubMed
Pahl, H L, Sester, M, Burgert, H G, Baeuerle, P A. Activation of transcription factor NFκB by the adenovirus E3/19K protein requires its ER retention. J Cell Biol 1996;132:511–22.CrossRefGoogle Scholar
Hu, C, Perlmutter, D H. Cell-specific involvement of HNF-1β in α-antitrypsin gene expression in human respiratory epithelial cells. Am J Physiol 2002;282:L757–65.Google Scholar
Pikarsky, E, Porat, R M, Stein, I. NFκB functions as a tumor promoter in inflammation-associated cancer. Nature 2004;431:461–6.CrossRefGoogle Scholar
Greten, F R, Eckman, L, Greten, T F. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004;118:285–96.CrossRefGoogle Scholar
Maeda, S, Kamata, H, Luo, J-L. IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 2005;121:977–90.CrossRefGoogle ScholarPubMed
Schamel, W W, Kuppig, S, Becker, B. A high-molecular-weight complex of membrane proteins BAP29/BAP31 is involved in the retention of membrane-bound IgD in the endoplasmic reticulum. Proc Natl Acad Sci U S A 2003;100:9861–6.CrossRefGoogle ScholarPubMed
Breckenridge, D G, Stojanovic, M, Marcellus, R C, Shore, G C. Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol 2003;160:1115–27.CrossRefGoogle ScholarPubMed
Povey, S. Genetics of α-antitrypsin deficiency in relation to neonatal liver disease. Mol Biol Med 1990;7:161–2.Google Scholar
Dougherty, D G, Donaldson, P T, Whitehouse, D B. HLA phenotype and gene polymorphism in juvenile liver disease associated with α-antitrypsin deficiency. Hepatology 1990;12:218–23.CrossRefGoogle Scholar
Lobo-Yeo, A, Senaldi, G, Portmann, R. Class I and class II major histocompatibility complex antigen expression on hepatocytes: a study in children with liver disease. Hepatology 1990;12:224–32.CrossRefGoogle Scholar
Sargent, C A, Dunham, I, Trowsdale, J. Human major histocompatibility complex contains genes for the major heat shock protein HSP 70. Proc Natl Acad Sci U S A 1989;1968–77.CrossRefGoogle Scholar
Albertella, M R, Jones, H, ThomsonW, et al W, et al. Localisation of eight additional genes in the human major histocompatibility complex, including the gene encoding the casein kinase II beta subunit, and DNA sequence analysis of the class III region. DNA Sequence 1996;7:9–12.CrossRefGoogle ScholarPubMed
Geller, S A, Nichols, W S, Dycacio, M J. Histopathology of α-antitrypsin liver disease in a transgenic mouse model. Hepatology 1990;12:40–7.CrossRefGoogle Scholar
Geller, S A, Nichols, W S, Kim, S S. Hepatocarcinogenesis is the sequel to hepatitis in Z#2 α-antitrypsin transgenic mice: histopathological and DNA ploidy studies. Hepatology 1994;19:389–97.CrossRefGoogle Scholar
Gaczynska, M, Rock, K L, Goldber, A L. Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature 1993;365:264–7.CrossRefGoogle ScholarPubMed
Bathurst, I C, Errington, D M, Foreman, R C. Human Z alpha-1-antitrypsin accumulates intracellularly and stimulates lysosomal activity when synthesized in the xenopus oocyte. FEBS Lett 1985;183:304–8.CrossRefGoogle Scholar
Raposo, G, Santen, H M, Liejendekker, R. Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment. J Cell Biol 1995;131:1403–19.CrossRefGoogle Scholar
Dunn, W A. Studies on the mechanism of autophagy: formation of autophagic vacuole. J Cell Biol 1991;110:1923–33.CrossRefGoogle Scholar
Mizushima, N, Noda, T, Yoshimori, T. A protein conjugation system essential for autophagy. Nature 1998;195:395–8.CrossRefGoogle Scholar
Klionsky, D J. Autophagy. Curr Biol 2005;15:R282–3.CrossRefGoogle ScholarPubMed
Johnston, J A, Ward, C L, Kopito, R R. Aggresomes: a cellular response to misfolded proteins. J Cell Biol 1998;143:1883–98.CrossRefGoogle ScholarPubMed
Anton, L C, Schubert, U, Bacik, I. Intracellular localization of proteasomal degradation of a viral antigen. J Cell Biol 1999;146:113–24.CrossRefGoogle ScholarPubMed
Teckman, J H, An, J-K, Loethen, S, Perlmutter, D H. Effect of fasting on liver in a mouse model of α-antitrypsin deficiency: constitutive activation of the autophagic response. Am J Physiol 2002;283:61117–24.Google Scholar
Tanka, Y, Guhde, G, Suter, A. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 2000;406:902–6.Google Scholar
Nishino, I, Fu, J, Tanji, K. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 2000;406:906–10.CrossRef
Elmore, S P, Qian, T, Grissom, D F, Lemasters, J J. The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J 2001;15:2286–7.CrossRefGoogle ScholarPubMed
Perkins, G, Renken, C, Martone, M E. Electron tomography of neuronal mitochondria: three-dimensional structure and organization of cristae and membrane contacts. J Struct Biol 1997;119:260–72.CrossRefGoogle ScholarPubMed
Achleitner, G, Gaigg, B, Krasser, A. Association between the endoplasmic reticulum and mitochondria of yeast facilitates interorganelle transport of phospholipids through membrane contact. Eur J Biochem 1999;264:545–53.CrossRefGoogle ScholarPubMed
Wang, H-J, Guay, G, Pogan, L. Calcium regulates the association between mitochondria and a smooth subdomain of the endoplasmic reticulum. J Cell Biol 2000;150:1489–97.CrossRefGoogle Scholar
Arnaudeau, S, Kelley, W L, Walsh, J V, Demaurex, N. Mitochondria recycle Ca2+ to the endoplasmic reticulum and prevent the depletion of neighboring endoplasmic reticulum regions. J Biol Chem 2001;276:29430–9.CrossRefGoogle Scholar
Hacki, J, Egger, L, Monney, L. Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 2000;19:2286–95.CrossRefGoogle ScholarPubMed
Wei, M C, Zong, W X, Cheng, E H. Proapoptotic BAX and BAK; a requisite gateway to mitochondrial dysfunction and death. Science 2001;292:727–30.CrossRefGoogle Scholar
Rudnick, D A, Liao, Y, An, J K. Analyses of hepatocellular proliferation in a mouse model of α1-antitrypsin deficiency. Hepatology 2004;39:1048–55.CrossRefGoogle Scholar
Bruey, J M, Ducasse, C, Bonniaud, P. Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol 2000;2:645–52.CrossRefGoogle ScholarPubMed
Perlmutter, D H, Schlesinger, M J, Pierce, J A. Synthesis of stress proteins is increased in individuals with homozygous PiZZ α1-antitrypsin deficiency and liver disease. J Clin Invest 1989;84:1555–61.CrossRefGoogle Scholar
Vogel, A, Berg, I E, Al-Dhalimy, M. Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death. Hepatology 2004;39:433–43.CrossRefGoogle ScholarPubMed
Kvittingen, E A, Rootwelt, H, Berger, R, Brandtzaeg, P. Self-induced correction of the genetic defect in tyrosinemia type I. J Clin Invest 1994;94:1657–61.CrossRefGoogle ScholarPubMed
Overturf, K, Al-Dhalimy, M, Tanguay, R. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat Genet 1996;12:266–73.CrossRefGoogle Scholar
Demers, S I, Russo, P, Lettre, F, Tanguay, R M. Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia. Hum Pathol 2003;34:1313–20.CrossRefGoogle Scholar
McLachlan, A, Milich, D R, Raney, A K. Expression of hepatitis B virus surface and core antigens: influences of pre-S and precore sequences. J Virol 1987;61:683–92.Google ScholarPubMed
Wang, H C, Wu, H C, Chen, C F. Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress. Am J Pathol 2003;163:2441–9.CrossRefGoogle ScholarPubMed
Dubuisson, J. Folding, assembly and subcellular localization of hepatitis C virus glycoproteins. Curr Top Microbiol Immunol 2000;242:135–48.Google ScholarPubMed
Yang, S Q, Lin, H Z, Hwang, J. Hepatic hyperplasia in noncirrhotic fatty livers: is obesity-related hepatic steatosis a premalignant condition?Cancer Res 2001;61:5016–23.Google ScholarPubMed
Roskams, T, Yang, S Q, Koteish, A. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol 2003;163:1301–11.CrossRefGoogle ScholarPubMed
Johnson, K, Alton, H M, Chapman, S. Evaluation of mebrofenin hepatoscintigraphy in neonatal-onset jaundice. Pediatr Radiol 1998;28:937–41.CrossRefGoogle ScholarPubMed
Nord, K S, Saad, S, Joshi, V V. Concurrence of α-antitrypsin deficiency and biliary atresia. J Pediatr 1987;111:416–18.CrossRefGoogle Scholar
Ghishan FK, Greene HL. Inborn errors of metabolism that lead to permanent liver injury. In: Zakim, D, Boyer, T D. Hepatology: a textbook of liver disease. Philadelphia: WB Saunders, 1982:1351.Google Scholar
Mowat AP. Hepatitis and cholestasis in infancy: intrahepatic disorders. In: Mowat, A P. Liver disorders in childhood. London: Butterworth, 1982:50.Google ScholarPubMed
Qizibash, A, Yong-Pong, O. Alpha-1-antitrypsin liver disease: differential diagnosis of PAS-positive diastase-resistant globules in liver cells. Am J Clin Pathol 1983;79:697–702.CrossRefGoogle Scholar
Yunis, E J, Agostini, R M, Glew, R H. Fine structural observations of the liver in α-antitryspin deficiency. Am J Clin Pathol 1976;82:265–86.Google ScholarPubMed
Tobin, M J, Cook, P J L, Hutchison, D C S. Alpha-1-antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. Br J Dis Chest 1983;77:14–27.CrossRefGoogle ScholarPubMed
Udall, J N, Dixon, M, Newman, A P. Liver disease in α-antitrypsin deficiency: a retrospective analysis of the influence of early breast- vs bottle-feeding. JAMA 1985;253:2679–82.CrossRefGoogle Scholar
Udall, J N, Bloch, K J, Walker, W A. Transport of proteases across neonatal intestine and development of liver disease in infants with α-antitrypsin deficiency. Lancet 1982;ii:1441–3.CrossRefGoogle Scholar
Kayler, L K, Merion, R M, Lee, S. Long-term survival after liver transplantation in children with metabolic disorders. Pediatr Transplant 2002;6:295–300.CrossRefGoogle ScholarPubMed
Gelfand, J A, Sherins, R J, Alling, D W. Treatment of hereditary angiodema with danazol: reversal of clinical and biochemical abnormalities. N Engl J Med 1976;195:1444–8.CrossRefGoogle Scholar
Gadek, J E, Fulmer, J D, Gelfand, J A. Danazol-induced augmentation of serum alpha-1-antitrypsin levels in individuals with marked deficiency of this anti-protease. J Clin Invest 1980;66:82–7.CrossRefGoogle Scholar
Wewers, M D, Gadek, J E, Loegh, B A. Evaluation of danazol therapy for patients with PiZZ alpha-1-antitrypsin deficiency. Am Rev Respir Dis 1986;134:476–80.Google ScholarPubMed
Sato, S, Ward, C L, Krouse, M E. Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J Biol Chem 1996;271:635–8.CrossRefGoogle ScholarPubMed
Tatzelt, J, Prusiner, S B, Welch, W J. Chemical chaperones interfere with the formation of scrapie prion protein. EMBO J 1996;15:6363–73.Google ScholarPubMed
Tamarappoo, B, Verkman, A S. Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J Clin Invest 1998;101:2257–67.CrossRefGoogle ScholarPubMed
Brown, C R, Hong-Brown, L Q, Welch, W J. Correcting temperature-sensitive protein folding defects. J Clin Invest 1997;99:1432–44.CrossRefGoogle ScholarPubMed
Fan, J-Q, Ishii, S, Asano, N. Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med 1999;5:112–15.CrossRefGoogle ScholarPubMed
Burrows, J A J, Willis, L K, Perlmutter, D H. Chemical chaperones mediate increased secretion of mutant α-antitrypsin (α-AT) Z: a potential pharmacological strategy for prevention of liver injury and emphysema in α-AT deficiency. Proc Natl Acad Sci U S A 2000;97:1796–801.CrossRefGoogle Scholar
Jacob, G S. Glycosylation inhibitors in biology and medicine. Curr Opin Struct Biol 1995;5:605–11.CrossRefGoogle ScholarPubMed
Zitzmann, N, Mehta, A S, Carrouee, S. Imino sugars inhibit the formation and secretion of bovine viral diarrhea virus, a pestivirus model of hepatitis C virus: implications for the development of broad-spectrum anti-hepatitis virus agents. Proc Natl Acad Sci U S A 1999;96:11878–82.CrossRefGoogle ScholarPubMed
Marcus, N Y, Perlmutter, D H. Glucosidase and mannosidase inhibitors mediate increased secretion of mutant α1-antitrypsin Z. J Biol Chem 2000;275:1987–92.CrossRefGoogle ScholarPubMed
Abboud, R T, Ford, G T, Chapman, K R. Emphysema in alpha1antitrypsin deficiency: Does replacement therapy affect outcome?Treat Respir Med 2005;4:1–8.CrossRefGoogle Scholar
Cassivi, S D, Meyers, B F, Battafarano, R J. Thirteen year experience in lung transplantation for emphysema. Ann Thorac Surg 2002;74:1663–9.CrossRefGoogle ScholarPubMed
Anderson, W F. The current status of clinical gene therapy. Hum Gene Ther 2002;13:1261–2.CrossRefGoogle ScholarPubMed
Long, M B, Jones, J P, Sullenger, B A, Byun, J. Ribozyme-mediated revision of RNA and DNA. J Clin Invest 2003;112:312–18.CrossRefGoogle ScholarPubMed
Garcia-Blanco, M A. Messenger RNA reprogramming by spliceosome-mediated RNA trans-splicing. J Clin Invest 2003;112:474–80.CrossRefGoogle ScholarPubMed
Kren, B T, Bandyopadhyay, P, Steer, C J. In vivo site-directed mutagenesis of the factor IX gene by chimeric RNA/DNA oligonucleotides. Nat Med 1998;4:285–90.CrossRefGoogle ScholarPubMed
Metz, R, Dicola, M, Kurihara, T. Mode of action of RNA/DNA oligonucleotides. Chest 2002;121:915–25.CrossRefGoogle ScholarPubMed
Kmiec, E B. Targeted gene repair – in the arena. J Clin Invest 2003;112:632–6.CrossRefGoogle ScholarPubMed
Seidman, M M, Glazier, P M. The potential for gene repair via triple helix formation. J Clin Invest 2003;114:487–94.CrossRefGoogle Scholar
Gruenert, D C, Bruscia, E, Novelli, G. Sequence-specific modification of genomic DNA by small DNA fragments. J Clin Invest 2003;112:637–41.CrossRefGoogle ScholarPubMed
Davidson, B L. Hepatic diseases – hitting the target with inhibitory RNAs. N Engl J Med 2003;349:2357–9.CrossRefGoogle ScholarPubMed
Rubinson, D A, Dillon, C P, Kwiatkowski, A V. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Gen 2003;33:401–6.CrossRefGoogle ScholarPubMed
Rhim, J A, Sandgen, E P, Degen, J L. Replacement of disease mouse liver by hepatic cell transplantation. Science 1994;263:1149–52.CrossRefGoogle Scholar
Day, P M, Yewdell, J W, Porgador, A. Direct delivery of exogenous MHC class I molecule-binding oligopeptides to the endoplasmic reticulum of viable cells. Proc Natl Acad Sci U S A 1997;94:8064–9.CrossRefGoogle ScholarPubMed
Johannes, L, Goud, B. Surfing on a retrograde wave: how does Shiga toxin reach the endoplasmic reticulum?Trends Cell Biol 1998;8:158–62.CrossRefGoogle ScholarPubMed
Lord,, J M, Roberts, L M. Toxin entry: retrograde transport through the secretory pathway. J Cell Biol 1998;140:733–6.CrossRefGoogle Scholar
Kidd, V J, Golbus, M S, Wallace, R B. Prenatal diagnosis of alpha-1-antitrypsin deficiency by direct analysis of the mutation site in the gene. N Engl J Med 1984;310:639–42.CrossRefGoogle ScholarPubMed
Cox, D W, Mansfield, T. Prenatal diagnosis of alpha-1-antitrypsin deficiency and estimates of fetal risk for disease. J Med Genet 1987;24:52–9.CrossRefGoogle ScholarPubMed
Nukiwa, T, Brantly, M, Garver, R. Evaluation of “at risk” alpha-1-antitrypsin genotype SZ with synthetic oligonucleotide gene probes. J Clin Invest 1986;77:528–37.CrossRefGoogle ScholarPubMed
Psacharopoulos, H T, Mowat, A P, Cook, P J L. Outcome of liver disease associated with alpha-1-antitrypsin deficiency (PiZ). Arch Dis Child 1983;58:882–7.CrossRefGoogle Scholar
Thelin, T, Sveger, T, McNeil, T F. Primary prevention in a high-risk group: smoking habits in adolescents with homozygous alpha-1-antitrypsin deficiency. Acta Paediatr 1996;85:1207–12.CrossRefGoogle Scholar
Wall, M, Moe, E, Eisenberg, J. Long-term follow-up of a cohort of children with alpha-1-antitrypsin deficiency. J Pediatr 1990;116:248–51.CrossRefGoogle ScholarPubMed
McNeil, T F, Sveger, T, Thelin, T. Psychosocial effects of screening for somatic risk: the Swedish α-antitrypsin experience. Thorax 1988;43:505–7.CrossRefGoogle Scholar
Sveger, T, Thelin, T, McNeil, T F. Young adults with α-antitrypsin deficiency identified neonatally: their health, knowledge about and adaptation to the high-risk condition. Acta Paediatr 1997;86:37–40.CrossRefGoogle Scholar

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  • α1-Antitrypsin Deficiency
    • By David H. Perlmutter, M.D., Vira I. Heinz Professor and Chair, Department of Pediatrics, Professor of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Physician-in-Chief and Scientific Director, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
  • Edited by Frederick J. Suchy, Mount Sinai School of Medicine, New York, Ronald J. Sokol, University of Colorado, Denver, William F. Balistreri, University of Cincinnati
  • Book: Liver Disease in Children
  • Online publication: 18 December 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511547409.025
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  • α1-Antitrypsin Deficiency
    • By David H. Perlmutter, M.D., Vira I. Heinz Professor and Chair, Department of Pediatrics, Professor of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Physician-in-Chief and Scientific Director, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
  • Edited by Frederick J. Suchy, Mount Sinai School of Medicine, New York, Ronald J. Sokol, University of Colorado, Denver, William F. Balistreri, University of Cincinnati
  • Book: Liver Disease in Children
  • Online publication: 18 December 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511547409.025
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  • α1-Antitrypsin Deficiency
    • By David H. Perlmutter, M.D., Vira I. Heinz Professor and Chair, Department of Pediatrics, Professor of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Physician-in-Chief and Scientific Director, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
  • Edited by Frederick J. Suchy, Mount Sinai School of Medicine, New York, Ronald J. Sokol, University of Colorado, Denver, William F. Balistreri, University of Cincinnati
  • Book: Liver Disease in Children
  • Online publication: 18 December 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511547409.025
Available formats
×