Polymorphism in the Endoplasmic Reticulum Mannosidase I (MAN1B1) Gene Is Not Associated with Liver Disease in Individuals Homozygous for the Z Variant of the Alpha1-Antitrypsin Protease Inhibitor (PiZZ Individuals)†

Pan, Shujuan; Sifers, Richard N.

doi:10.1002/hep.23193

Hepatology

2009

DOI: 10.1002/hep.23193

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Polymorphism in the Endoplasmic Reticulum Mannosidase I (MAN1B1) Gene Is Not Associated with Liver Disease in Individuals Homozygous for the Z Variant of the Alpha1-Antitrypsin Protease Inhibitor (PiZZ Individuals)†

Shujuan Pan

Richard N. Sifers

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2012

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“…Consistent with this hypothesis, a candidate genesequencing study of endoplasmic reticulum (ER) mannosidase I (ERManI), which facilitates the degradation of misfolded secreted proteins (Hosokawa et al 2003;Wu et al 2003), suggested that differences in ERManI expression are associated with earlier age-of-onset of end-stage liver disease ). However, because of the small number of samples available for study, the significance of this association has been challenged (Chappell et al 2009;Pan and Sifers 2009). Even if the ERManI polymorphism does not prove to be a clinically significant modifier of ATD, there are likely to be many other factors that modify ATD-associated liver disease.…”

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The Endosomal Protein-Sorting Receptor Sortilin Has a Role in Trafficking α-1 Antitrypsin

et al. 2012

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Up to 1 in 3000 individuals in the United States have a-1 antitrypsin deficiency, and the most common cause of this disease is homozygosity for the antitrypsin-Z variant (ATZ). ATZ is inefficiently secreted, resulting in protein deficiency in the lungs and toxic polymer accumulation in the liver. However, only a subset of patients suffer from liver disease, suggesting that genetic factors predispose individuals to liver disease. To identify candidate factors, we developed a yeast ATZ expression system that recapitulates key features of the disease-causing protein. We then adapted this system to screen the yeast deletion mutant collection to identify conserved genes that affect ATZ secretion and thus may modify the risk for developing liver disease. The results of the screen and associated assays indicate that ATZ is degraded in the vacuole after being routed from the Golgi. In fact, one of the strongest hits from our screen was Vps10, which can serve as a receptor for the delivery of aberrant proteins to the vacuole. Because genome-wide association studies implicate the human Vps10 homolog, sortilin, in cardiovascular disease, and because hepatic cell lines that stably express wild-type or mutant sortilin were recently established, we examined whether ATZ levels and secretion are affected by sortilin. As hypothesized, sortilin function impacts the levels of secreted ATZ in mammalian cells. This study represents the first genome-wide screen for factors that modulate ATZ secretion and has led to the identification of a gene that may modify disease severity or presentation in individuals with ATZ-associated liver disease.A N inherited disorder, a-1 AT deficiency (ATD) is linked to decreased levels and activity of the proteinase inhibitor a-1 antitrypsin (AT). It is one of the most common genetic disorders in the United States, with the most severe form affecting between 1 in 3000 and 1 in 6000 individuals (Kimpen et al. 1988;Silverman et al. 1989;Spence et al. 1993;de Serres et al. 2007de Serres et al. , 2010.Wild-type AT (referred to here as the M variant, or ATM) is an abundant plasma protein secreted by hepatocytes that protects lung tissue from the action of neutrophil elastase. The most common cause of ATD is homozygosity for the mutation that gives rise to the Z variant of AT (ATZ), which exhibits folding and thus secretion defects. Retention of ATZ within hepatocytes results in AT deficiency in the lungsconsidered a loss-of-function phenotype-but can also result in an accumulation of polymeric and aggregated ATZ within the liver, which manifests as a gain-of-function phenotype (Bathurst et al. 1984Foreman et al. 1984;Errington et al. 1985;Janus et al. 1985; Perlmutter et al. 1985a,b;Dycaico et al. 1988;Carlson et al. 1989;Lomas et al. 1992). These organ-specific effects of ATZ are consequently responsible for the two most common clinical manifestations of ATD, lung disease and liver disease.Interestingly, there is considerable variability in the ageof-onset and severity of these diseases, particular...

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The Endosomal Protein-Sorting Receptor Sortilin Has a Role in Trafficking α-1 Antitrypsin

et al. 2012

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Polymorphism in the Endoplasmic Reticulum Mannosidase I (MAN1B1) Gene Is Not Associated with Liver Disease in Individuals Homozygous for the Z Variant of the Alpha1-Antitrypsin Protease Inhibitor (PiZZ Individuals)†

Abstract: References

Cited by 1 publication

References 6 publications

The Endosomal Protein-Sorting Receptor Sortilin Has a Role in Trafficking α-1 Antitrypsin

The Endosomal Protein-Sorting Receptor Sortilin Has a Role in Trafficking α-1 Antitrypsin

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