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

Abstract

UNLABELLED:

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.

• Authors: Shujuan Pan, Lu Huang, John McPherson, Donna Muzny, Farshid Rouhani, Mark Brantly, Richard Gibbs, Richard N Sifers
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 50 Issue 1 Pg. 275-81 (Jul 2009) ISSN: 1527-3350 [Electronic] United States
• PMID: 19444872 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Mannosidases
• endoplasmic reticulum alpha-mannosidase I, human

Topics

• Adolescent
• Adult
• Age of Onset
• Cells, Cultured
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Liver Failure (genetics)
• Male
• Mannosidases (genetics)
• Middle Aged
• Polymorphism, Single Nucleotide (genetics)
• Protein Biosynthesis
• alpha 1-Antitrypsin Deficiency (genetics)