Molecular pathogenesis of liver disease in ?1-antitrypsin deficiency

Teckman, Jeffrey; Qu, Dongfeng; Perlmutter, David H.

doi:10.1002/hep.510240635

Cited by 46 publications

(43 citation statements)

References 125 publications

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“…Since homozygosity for PI Z causes severe liver disease in a subset of patients, 7,38 this raises the question of hepatocellular damage in compound heterozygous carriers of the Mwürzburg or Mheerlen mutations in combination with the frequent Z allele, if these individuals are 'susceptible' to a1AT-induced liver disease. [21][22][23] Our patient with the Mheerlen mutation was heterozygous for the non-expressing null-allele Q0granite falls, 20,31 had extremely low α1AT serum level and severe COPD, but no evidence of liver disease. The heterozygous carrier of the Mwürzburg mutation also had no signs of liver injury.…”

Section: And Wild-type M1 Protein In the Cell Lysates Is Shown With (mentioning

confidence: 79%

“…Although a long-term study of PI ZZ homozygotes has shown that 37% of these individuals ultimately suffer from liver cirrhosis and that 15% additionally develop primary hepatocellular carcinoma, 12 the question whether the PI Mheerlen and Mwürzburg alleles can trigger liver disease in PI Z compound heterozygotes remains to be answered. The key experiment towards this end will be expression of the mutant alleles in fibroblasts from PI ZZ patients with liver disease ('susceptible hosts' according to Perlmutter 21,22 ) and from PI ZZ individuals without liver disease ('protected hosts').…”

Section: And Wild-type M1 Protein In the Cell Lysates Is Shown With (mentioning

confidence: 99%

“…20 Interestingly, only a minor fraction of the patients with intracellular α1AT accumulation actually develops liver disease. There is evidence that in addition to the PI ZZ genotype a defect in a common endoplasmic reticulum (ER) protein degradation pathway is required to trigger the hepatopathy, [21][22][23] and that patients without that defect are protected against liver damage by the mutant α1AT. 11% of children with the PI ZZ phenotype develop cholostatic icterus and 2-3% of them die of liver cirrhosis before the age of 8 years.…”

Section: Introductionmentioning

confidence: 99%

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Molecular characterisation of the defective α1-antitrypsin alleles PI Mwürzburg (Pro369Ser), Mheerlen (Pro369Leu), and Q0lisbon (Thr68lle)

et al. 1999

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Deficiency of the serine proteinase inhibitor (serpin) α1-antitrypsin (α1AT) is the most common autosomal recessive genetic disorder in Northern Europe. α1AT is the physiological regulator of the proteolytic enzyme neutrophil elastase and severe deficiency states are associated with an increased risk of developing chronic obstructive pulmonary disease (COPD) as a consequence of chronic proteolytic damage to the lungs. Among the known mutations of the α1AT gene causing severe α1AT deficiency and COPD a few alleles are also associated with liver disease. When expressed in cell cultures, all these particular alleles cause intracellular α1AT accumulation which appears to be a prerequisite for the development of hepatic injury. Liver disease is seen in only a small fraction of all patients carrying such alleles, however. The reason for this is not completely clear, but there is evidence that PI ZZ individuals 'susceptible' to liver disease carry an additional defect affecting protein degradation in the endoplasmic reticulum (ER). We characterise a newly identified defective http://www.stockton-press.co.uk/ejhg Mheerlen α1ATs are completely retained within synthesising cells, and the molecular defect of transportation in these two alleles may be similar to that in the common PI Z allele. The molecular defect in the PI Q0lisbon allele (Thr68Ile) shows similarity with the immediately neighbouring Mmineral springs mutation (Gly67Glu).

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Section: And Wild-type M1 Protein In the Cell Lysates Is Shown With (mentioning

confidence: 79%

Section: And Wild-type M1 Protein In the Cell Lysates Is Shown With (mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular characterisation of the defective α1-antitrypsin alleles PI Mwürzburg (Pro369Ser), Mheerlen (Pro369Leu), and Q0lisbon (Thr68lle)

et al. 1999

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“…The principal role of ␣ 1 -AT in serum is to protect lung tissues from destructive proteases (elastase, cathepsin G, and proteinase 3) released by neutrophils during inflammation. Some genetic alterations in ␣ 1 -AT are responsible for defective secretion and thus cause serum ␣ 1 -AT deficiency (1)(2)(3). The most common causal mutation found in Caucasian populations is the replacement of Glu-342 by Lys that characterizes the Z mutant of ␣ 1 -AT (␣ 1 -ATZ).…”

mentioning

confidence: 99%

Intracellular Inclusions Containing Mutant α1-Antitrypsin Z Are Propagated in the Absence of Autophagic Activity

Kamimoto

Shoji

Hidvegi

et al. 2006

Journal of Biological Chemistry

249

261

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Mutant ␣ 1 -antitrypsin Z (␣ 1 -ATZ) protein, which has a tendency to form aggregated polymers as it accumulates within the endoplasmic reticulum of the liver cells, is associated with the development of chronic liver injury and hepatocellular carcinoma in hereditary ␣ 1 -antitrypsin (␣ 1 -AT) deficiency. Previous studies have suggested that efficient intracellular degradation of ␣ 1 -ATZ is correlated with protection from liver disease in ␣ 1 -AT deficiency and that the ubiquitin-proteasome system accounts for a major route, but not the sole route, of ␣ 1 -ATZ disposal. Yet another intracellular degradation system, autophagy, has also been implicated in the pathophysiology of ␣ 1 -AT deficiency. To provide genetic evidence for autophagy-mediated disposal of ␣ 1 -ATZ, here we used cell lines deleted for the Atg5 gene that is necessary for initiation of autophagy. In the absence of autophagy, the degradation of ␣ 1 -ATZ was retarded, and the characteristic cellular inclusions of ␣ 1 -ATZ accumulated. In wild-type cells, colocalization of the autophagosomal membrane marker GFP-LC3 and ␣ 1 -ATZ was observed, and this colocalization was enhanced when clearance of autophagosomes was prevented by inhibiting fusion between autophagosome and lysosome. By using a transgenic mouse with liver-specific inducible expression of ␣ 1 -ATZ mated to the GFP-LC3 mouse, we also found that expression of ␣ 1 -ATZ in the liver in vivo is sufficient to induce autophagy. These data provide definitive evidence that autophagy can participate in the quality control/degradative pathway for ␣ 1 -ATZ and suggest that autophagic degradation plays a fundamental role in preventing toxic accumulation of ␣ 1 -ATZ.3 a monomeric 394-amino acid glycoprotein, is synthesized and secreted primarily by liver cells. It is a prototypic member of serine protease inhibitor (serpin) superfamily proteins and the most abundant of the circulating serpins. The principal role of ␣ 1 -AT in serum is to protect lung tissues from destructive proteases (elastase, cathepsin G, and proteinase 3) released by neutrophils during inflammation. Some genetic alterations in ␣ 1 -AT are responsible for defective secretion and thus cause serum ␣ 1 -AT deficiency (1-3). The most common causal mutation found in Caucasian populations is the replacement of Glu-342 by Lys that characterizes the Z mutant of ␣ 1 -AT (␣ 1 -ATZ). This substitution is sufficient to cause an abnormality in folding early in the secretory pathway with retention of the mutant ␣ 1 -ATZ molecule in the ER of liver cells. Homozygotes for the ␣ 1 -ATZ mutation (PIZZ) are characterized by serum levels of ␣ 1 -AT that are ϳ10 -15% of those in the general population and are susceptible to two major target organ injuries. Destructive lung disease/emphysema in adults is due to a loss-of-function mechanism. Chronic liver disease often first discovered in childhood, but also affecting adults, is due to a gain-of-toxic-function mechanism in which liver cell injury results from the hepatotoxic effects of retained ␣ 1 -ATZ...

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“…Alternatively, there is no uniformly accepted mechanism explaining the pathophysiology of liver injury, although there is general agreement that it is linked to intracellular accumulation of mutant ␣ 1 AT. 14,15 Amino acid substitutions in the ␣ 1 AT molecule lead to abnormal folding and accumulation of ␣ 1 AT within cellular endoplasmic reticulum, a process that may be further aggravated by defective degradation of the aggregated mutant molecules in some individuals. [16][17][18][19][20] The ''accumulation theory'' is further supported by the fact that liver disease has not been described in humans with the rare ''null'' variants (PI*Q0), who are incapable of synthesizing ␣ 1 AT and therefore do not have intracellular accumulation.…”

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confidence: 99%

Increased risk of chronic liver failure in adults with heterozygous ?-antitrypsin deficiency

Graziadei¹,

Joseph²,

Wiesner³

et al. 1998

Hepatology

132

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Controversy exists whether patients who are genetically heterozygous for ␣ 1 -antitrypsin deficiency (␣ 1 ATD), carrying a single PI*Z allele, are at increased risk of developing chronic liver disease. In these investigations, we determined the prevalence of heterozygous ␣ 1 AT phenotypes (PI MZ, PI SZ) in a well-characterized cohort of patients presenting with chronic liver failure before orthotopic liver transplantation (OLT). We analyzed data collected from all adult patients (n ‫؍‬ 641) who underwent OLT at our tertiary referral center between March 1985 and December 1996. Study patients entered a prospective protocol designed to test for all known etiologies of liver disease. Complete testing including ␣ 1 AT phenotyping was successfully performed in 599 adults. We compared the overall number of heterozygous PI*Z carriers in our OLT cohort with established prevalence figures for general and regional American populations, and examined their distribution among various liver disease subgroups. Fifty-one patients were found to be heterozygous carriers of a single PI*Z allele for ␣ 1 AT. The predominant phenotype in our transplantation cohort was PI MZ, identified in 49 patients (8.2%), which is a significantly higher prevalence than that reported from previous American population studies (2%-4%). Additionally, a significantly greater number of PI MZ carriers existed in patients with cryptogenic cirrhosis compared with other liver disease categories (26.9%; P F .001). These data suggest that individuals carrying a single PI*Z allele for ␣ 1 AT may be at increased risk of developing cirrhosis and liver failure, even in the absence of an identifiable coexisting liver disease. (HEPATOLOGY 1998;28:1058-1063

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Molecular pathogenesis of liver disease in ?1-antitrypsin deficiency

Cited by 46 publications

References 125 publications

Molecular characterisation of the defective α1-antitrypsin alleles PI Mwürzburg (Pro369Ser), Mheerlen (Pro369Leu), and Q0lisbon (Thr68lle)

Molecular characterisation of the defective α1-antitrypsin alleles PI Mwürzburg (Pro369Ser), Mheerlen (Pro369Leu), and Q0lisbon (Thr68lle)

Intracellular Inclusions Containing Mutant α1-Antitrypsin Z Are Propagated in the Absence of Autophagic Activity

Increased risk of chronic liver failure in adults with heterozygous ?-antitrypsin deficiency

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