Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency

Shujuan Pan, Lu Huang, John Douglas Mcpherson, Donna Muzny, Farshid Rouhani, Mark Brantly, Richard Gibbs, Richard N. Sifers

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Inappropriate accumulation of the misfolded Z variant of alpha1-antitrypsin in the hepatocyte endoplasmic reticulum (ER) is a risk factor for the development of end-stage liver disease. However, the genetic and environmental factors that contribute to its etiology are poorly understood. ER mannosidase I (ERManI) is a quality control factor that plays a critical role in the sorting and targeting of misfolded glycoproteins for proteasome-mediated degradation. In this study, we tested whether genetic variations in the human ERManI gene influence the age at onset of end-stage liver disease in patients homozygous for the Z allele (ZZ). We sequenced all 13 exons in a group of unrelated Caucasian ZZ transplant recipients with different age at onset of the end-stage liver disease. Homozygosity for the minor A allele at 2484G/A (refSNP ID number rs4567) in the 3′-untranslated region was prevalent in the infant ZZ patients. Functional studies indicated that rs4567(A), but not rs4567(G), suppresses ERManI translation under ER stress conditions. Conclusion: These findings suggest that the identified single-nucleotide polymorphism can accelerate the onset of the end-stage liver disease associated with alpha1-antitrypsin deficiency and underscore the contribution of biosynthetic quality control as a modifier of genetic disease.

Original languageEnglish (US)
Pages (from-to)275-281
Number of pages7
JournalHepatology
Volume50
Issue number1
DOIs
StatePublished - 2009
Externally publishedYes

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mannosyl-oligosaccharide 1,2-alpha-mannosidase
End Stage Liver Disease
Endoplasmic Reticulum
Single Nucleotide Polymorphism
Age of Onset
Quality Control
Alleles
Inborn Genetic Diseases
Endoplasmic Reticulum Stress
3' Untranslated Regions
Proteasome Endopeptidase Complex
Hepatocytes
Exons
Glycoproteins
Genes

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency. / Pan, Shujuan; Huang, Lu; Mcpherson, John Douglas; Muzny, Donna; Rouhani, Farshid; Brantly, Mark; Gibbs, Richard; Sifers, Richard N.

In: Hepatology, Vol. 50, No. 1, 2009, p. 275-281.

Research output: Contribution to journalArticle

Pan, Shujuan ; Huang, Lu ; Mcpherson, John Douglas ; Muzny, Donna ; Rouhani, Farshid ; Brantly, Mark ; Gibbs, Richard ; Sifers, Richard N. / Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency. In: Hepatology. 2009 ; Vol. 50, No. 1. pp. 275-281.
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