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1
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10844258104
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Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization
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Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306:2090-2093. Presents data supporting a model whereby hepcidin directly stimulates the internalization of ferroportin, an iron exporter on the surface of hepatocytes, macrophages, and hepatocytes. The authors propose a homeostatic process whereby increased plasma iron, by stimulating the production of hepcidin by hepatocytes, reduces iron uptake by internalization of ferroportin and a consequent rise in cytoplasmic iron levels, thus effecting reduced iron uptake by affected cells.
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(2004)
Science
, vol.306
, pp. 2090-2093
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Nemeth, E.1
Tuttle, M.S.2
Powelson, J.3
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2
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24344462594
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Iron stores modulate hepatic hepcidin expression by an HFE-independent pathway
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Gehrke SG, Herrmann T, Kulaksiz H, et al. Iron stores modulate hepatic hepcidin expression by an HFE-independent pathway. Digestion 2005; 72: 25-32. This paper examines whether the hepatic expression of HAMP (encoding hepcidin) requires the involvement of HFE or other iron-related genes.
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(2005)
Digestion
, vol.72
, pp. 25-32
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Gehrke, S.G.1
Herrmann, T.2
Kulaksiz, H.3
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3
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13544250486
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Hepcidin is decreased in TFR2 hemochromatosis
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Nemeth E, Roetto A, Garozzo G, et al. Hepcidin is decreased in TFR2 hemochromatosis. Blood 2005; 105:1803-1806. Using patients with TFR2 mutation-related hemochromatosis, the authors demonstrated that TFR2 modulates hepcidin production in response to iron.
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(2005)
Blood
, vol.105
, pp. 1803-1806
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Nemeth, E.1
Roetto, A.2
Garozzo, G.3
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4
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28844506080
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Limited iron export by hepatocytes contributes to hepatic iron-loading in the Hfe knockout mouse
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Chua ACG, Drake SF, Herbison CE, et al. Limited iron export by hepatocytes contributes to hepatic iron-loading in the Hfe knockout mouse. J Hepatol 2006; 44:176-182. This article endeavored to determine the role that ferroportin expression and iron release, as opposed to iron uptake, play in hemochromatosis by looking at iron release and ferroportin expression in HFE-knockout mice.
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(2006)
J Hepatol
, vol.44
, pp. 176-182
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Acg, C.1
Drake, S.F.2
Herbison, C.E.3
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5
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14944345916
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Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes
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Pietrangelo A, Caleffi A, Henrion J, et al. Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology 2005; 128:470-479. This paper studied a family with siblings who clinically appeared to have juvenile hemochromatosis, but lacked HJV mutations and were compound heterozygotes for C282Y/H63D and possessed TFR2 mutations. These data stress the multigenic modulation of the phenotypic expression of iron-overload disorders.
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(2005)
Gastroenterology
, vol.128
, pp. 470-479
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Pietrangelo, A.1
Caleffi, A.2
Henrion, J.3
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6
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27844451495
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Hemochromatosis gene HFE Cys282Tyr mutation analysis in a cohort of northeast German hospitalized patients supports assumption of a north to south allele frequency gradient throughout Germany
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Meier P, Schuff-Werner P, Steiner M. Hemochromatosis gene HFE Cys282Tyr mutation analysis in a cohort of northeast German hospitalized patients supports assumption of a north to south allele frequency gradient throughout Germany. Clin Lab 2005; 51:539-543. A genetic-epidemiological study that supports the concept of geographic gradients in HFE mutations. Such gradients lend credence to hypotheses about the spread of HFE mutations through northern Europe by northern European peoples such as the Celts and Norse.
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(2005)
Clin Lab
, vol.51
, pp. 539-543
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Meier, P.1
Schuff-Werner, P.2
Steiner, M.3
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7
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26244440542
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Phenotype variation in C282Y homozygotes for the hemochromatosis gene
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Lazarescu A, Snively BM, Adams PC. Phenotype variation in C282Y homozygotes for the hemochromatosis gene. Clin Gastroenterol Hepatol 2005; 3:1043-1046. By performing regression analysis to search for factors that could modify the tendency of HFE mutations to result in clinically apparent iron overload, the authors found that only male sex, increasing age, and the absence of a non-expressor in the family were associated with disease expression. Furthermore, they found that a significant variance was still noted when adjusting for age, sex, and genotype, supporting the idea that as yet unknown factors play a factor in disease expression as well.
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(2005)
Clin Gastroenterol Hepatol
, vol.3
, pp. 1043-1046
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Lazarescu, A.1
Snively, B.M.2
Adams, P.C.3
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8
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33645121766
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Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients
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in press
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McCune CA, Ravine D, Carter K, et al. Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients. Gut 2006 (in press).
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(2006)
Gut
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McCune, C.A.1
Ravine, D.2
Carter, K.3
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9
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20244372858
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Hemochromatosis and iron-overload screening in a racially diverse population
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Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005; 352:1769-1778. A product of the Hemochromatosis and Iron Overload Screening (HEIRS) study which examined the prevalence of HFE mutations and serum ferritin levels and transferrin saturations among different racial groups.
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(2005)
N Engl J Med
, vol.352
, pp. 1769-1778
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Adams, P.C.1
Reboussin, D.M.2
Barton, J.C.3
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10
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23244463800
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Survival after liver transplantation in patients with hepatic iron overload
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Kowdley KV, Brandhagen DJ, Gish RG, et al. Survival after liver transplantation in patients with hepatic iron overload. Gastroenterology 2005; 129: 494-503. An important paper showing that survival after liver transplantation is negatively impacted by genetic hemochromatosis. The paper also suggested that non-genetic hemochromatosis-related iron overload may also be associated with decreased survival following liver transplantation suggesting that early detection of iron overload prior to transplantation followed by iron-depletion therapy could positively impact posttransplant survival in both genetic hemochromatosis and non-genetic hemochromatosis groups.
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(2005)
Gastroenterology
, vol.129
, pp. 494-503
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Kowdley, K.V.1
Brandhagen, D.J.2
Gish, R.G.3
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11
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11244355277
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Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance
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St. Pierre TG, Clark PR, Chua-anusorn W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 2005; 105:855-861. The authors demonstrated improved methodology for measurement of iron overload in the liver using magnetic resonance imaging.
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(2005)
Blood
, vol.105
, pp. 855-861
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St. Pierre, T.G.1
Clark, P.R.2
Chua-anusorn, W.3
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12
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23844470848
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Early diagnosis of hemochromatosis-related cardiomyopathy with magnetic resonance imaging
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Ptaszek LM, Price ET, Hu MY, et al. Early diagnosis of hemochromatosis-related cardiomyopathy with magnetic resonance imaging. J Cardiovasc Magn Reson 2005; 7:689-692. This paper also demonstrates the potential application of magnetic resonance imaging in the diagnosis of hemochromatosis. In this case, the authors used magnetic resonance imaging to detect hemochromatosis-related cardiomyopathy in a patient undergoing workup for liver transplantation.
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(2005)
J Cardiovasc Magn Reson
, vol.7
, pp. 689-692
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Ptaszek, L.M.1
Price, E.T.2
Hu, M.Y.3
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13
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15744392287
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The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum
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Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S. The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum. J Biol Chem 2005; 280:9640-9645. These studies used the mouse knockout model of Wilson's disease to explore the relationship between the expression of the ATP7B, ATP7A, and ceruloplasmin in the cerebellum. The studies show cell-specific expression and function of ATP7A and ATP7B in the brain and cellular adaptation when ATP7b is absent.
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(2005)
J Biol Chem
, vol.280
, pp. 9640-9645
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Barnes, N.1
Tsivkovskii, R.2
Tsivkovskaia, N.3
Lutsenko, S.4
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14
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10244245059
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Hepatocellular carcinoma associated with Wilson's disease
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Iwadate H, Ohira H, Suzuki T, et al. Hepatocellular carcinoma associated with Wilson's disease. Intern Med 2004; 43:1042-1045. Case report of advanced HCC in a 23-year-old patient with Wilson's disease who presented with variceal bleeding after treatment with only 400 mg daily of D-penicillamine for 6 years after the diagnosis was established. A review of the literature showed only 11 reported cases of HCC in patients with Wilson's disease ranging in age from 14 to 61 years and treated from 1 week to 33 years. The true incidence of HCC remains to be determined in this population.
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(2004)
Intern Med
, vol.43
, pp. 1042-1045
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Iwadate, H.1
Ohira, H.2
Suzuki, T.3
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15
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0042329793
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Abdominal malignancies in patients with Wilson's disease
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Walshe JM, Waldenstrom E, Sams V, et al. Abdominal malignancies in patients with Wilson's disease. QJM 2003; 96:657-662.
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(2003)
QJM
, vol.96
, pp. 657-662
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Walshe, J.M.1
Waldenstrom, E.2
Sams, V.3
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17
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14244260491
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Wilson disease in septuagenarian siblings: Raising the bar for diagnosis
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Ala A, Borjigin J, Rochwarger A, Schilsky M. Wilson disease in septuagenarian siblings: raising the bar for diagnosis. Hepatology 2005; 41:668-670. Case report of two octogenarian siblings diagnosed late in life with different clinical presentations of their Wilson's disease. Identical mutations suggest environmental and hormonal influences modify disease expression. Late presentation of milder disease in one brings into question the degree of whether disease penetrance is truly 100%.
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(2005)
Hepatology
, vol.41
, pp. 668-670
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Ala, A.1
Borjigin, J.2
Rochwarger, A.3
Schilsky, M.4
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18
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10644252548
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Elastosis perforans serpiginosa associated with pseudo-pseudoxanthoma elasticum during treatment of Wilson's disease with penicillamine
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Becuwe C, Dalle S, Ronger-Savle S, et al. Elastosis perforans serpiginosa associated with pseudo-pseudoxanthoma elasticum during treatment of Wilson's disease with penicillamine. Dermatology 2005; 210:60-63.
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(2005)
Dermatology
, vol.210
, pp. 60-63
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Becuwe, C.1
Dalle, S.2
Ronger-Savle, S.3
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19
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19944430360
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Removal of metabolites, cytokines and hepatic growth factors by extracorporeal liver support in children
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Auth MK, Kim HS, Beste M, et al. Removal of metabolites, cytokines and hepatic growth factors by extracorporeal liver support in children. J Pediatr Gastroenterol Nutr 2005; 40:54-59. The concentrations of a number of growth factors and cytokines considered important for hepatic regeneration were evaluated in two pediatric patients with acute fulminant Wilson's disease treated with MARS prior to liver transplantation for two consecutive days. The data suggest that further careful prospective evaluation of patients undergoing interventions for treatment of acute liver failure is needed.
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(2005)
J Pediatr Gastroenterol Nutr
, vol.40
, pp. 54-59
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Auth, M.K.1
Kim, H.S.2
Beste, M.3
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20
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11244327849
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Contribution of Va24Vb11 natural killer T cells in Wilsonian hepatitis
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Kinebuchi M, Matsuura A, Ohya K, et al. Contribution of Va24Vb11 natural killer T cells in Wilsonian hepatitis. Clin Exp Immunol 2005; 139:144-151. An increase in the NK cell population was shown in the livers of three patients with Wilson's disease, one with fulminant liver injury. The numbers of the NK cells was decreased with treatment for Wilson's disease with medication or transplantation. A similar increase in NK cell population with increasing inflammation was shown in the livers of LEC rats, a rodent model of liver injury with Wilson's disease. Whether the change in the population of NK cells with inflammation is primary or secondary is uncertain.
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(2005)
Clin Exp Immunol
, vol.139
, pp. 144-151
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Kinebuchi, M.1
Matsuura, A.2
Ohya, K.3
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21
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16844379095
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Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency
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Bowlus CL, Willner I, Zern MA, et al. Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency. Clin Gastroenterol Hepatol 2005; 3:390-396. Survey by questionnaire of a cohort of patients in the Alpha-1 Foundation Registry with liver disease. Sixty-five of 2175 participants had a history of jaundice or liver disease; 71.3% were PiZZ, 18.0% were PiMZ, and 5.7% were of unknown phenotype. Advanced liver disease was associated with male gender and a higher mean body mass index, but not with race, Pi phenotype, or the presence of infant jaundice, diabetes, or hypercholesterolemia. Viral hepatitis was more frequent in the non-transplant group (34.7%), and the mean daily alcohol use was also significantly greater in this group. These results suggest that male gender and obesity predispose to advanced liver disease in adults with AAT deficiency, and confirm the heterogeneity of disease among patients with AAT deficiency.
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(2005)
Clin Gastroenterol Hepatol
, vol.3
, pp. 390-396
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Bowlus, C.L.1
Willner, I.2
Zern, M.A.3
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22
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28244499949
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Accumulation of mutant {alpha}1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NF{kappa}B, and BAP31 but not the unfolded protein response
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Hidvegi T, Schmidt BZ, Hale P, Perlmutter DH. Accumulation of mutant {alpha}1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NF{kappa}B, and BAP31 but not the unfolded protein response. J Biol Chem 2005; 280:39002-390015. The effect of mutant AATZ on potential protective signaling pathways was examined using cell lines with inducible expression of mutant AAT and liver from transgenic mice with liver-specific inducible expression of mutant AAT. Endoplasmic reticulum retention of polymerogenic mutant AATZ did not result in an unfolded protein response; however, endoplasmic reticulum retention of non-polymerogenic AAT mutants did induce such a response, indicating that activation of the unfolded protein response occurs for misfolded but not relatively ordered polymeric structures. Accumulation of mutant AATZ activated specific signaling pathways involved in apoptosis, including caspase-12 in mouse, caspase-4 in human, nuclear factor κB, and BAP31, a profile distinct from that activated by nonpolymerogenic AAT mutants.
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(2005)
J Biol Chem
, vol.280
, pp. 39002-390015
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Hidvegi, T.1
Schmidt, B.Z.2
Hale, P.3
Perlmutter, D.H.4
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23
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24044535062
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Grp78, Grp94, and Grp 170 interact with alpha1-antitrypsin mutants that are retained in the endoplasmic reticulum
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Schmidt BZ, Perlmutter DH. Grp78, Grp94, and Grp 170 interact with alpha1-antitrypsin mutants that are retained in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol 2005; 289:G444-G455. Chemical crosslinking of several different genetically engineered cell systems revealed mutant AATZ crosslinked with Grp78, Grp94, calnexin, Grp170, UDP-glucose glycoprotein:glucosyltransferase, and two unknown proteins ∼110-130 kDa. Sequential immunoprecipitation and immunoblot analysis and co- immunoprecipitation techniques also demonstrated these interactions. By contrast, the same chaperones interacted with two nonpolymerogenic AAT mutants retained in the endoplasmic reticulum, indicating that these interactions are not specific for the AATZ mutant. Approximately 85% of AATZ was found in heterogeneous soluble complexes with multiple chaperones; approximately 15% comprised extremely large polymers/aggregates devoid of chaperones. Agents that alter the synthesis or activity of endoplasmic reticulum chaperones such as tunicamycin and calcium ionophore A23187, have different effects on the solubility and degradation of AATZ as well as on its residual secretion. In summary, these studies identified similarities and differences between chaperones that interact with AATZ and other AAT mutants during their processing in the endoplasmic reticulum.
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(2005)
Am J Physiol Gastrointest Liver Physiol
, vol.289
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Schmidt, B.Z.1
Perlmutter, D.H.2
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24
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24144496018
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Alpha-1-antitrypsin deficiency: A new paradigm for hepatocellular carcinoma in genetic liver disease
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Rudnick DA, Perlmutter DH. Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatology 2005; 42:514-521. These authors observed that cells with accumulated mutant AATZ survive with intrinsic damage chronically stimulate adjacent relatively undamaged cells with a survival advantage, thus leading to the development of hepatocellular carcinoma. These authors propose this mechanism as a paradigm that may apply to other genetic and infectious liver diseases predisposed to HCC.
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(2005)
Hepatology
, vol.42
, pp. 514-521
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Rudnick, D.A.1
Perlmutter, D.H.2
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