title: Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency.
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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Pan
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.forename: John
authors.initials: J
authors.lastname: McPherson
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.forename: Farshid
authors.initials: F
authors.lastname: Rouhani
authors.forename: Mark
authors.initials: M
authors.lastname: Brantly
authors.forename: Richard
authors.initials: R
authors.lastname: Gibbs
authors.forename: Richard N
authors.initials: RN
authors.lastname: Sifers
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D017093:Liver Failure / Q000235:genetics*; D008297:Male; D008361:Mannosidases / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014176:Protein Biosynthesis; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics*
chemical_list: D008361:Mannosidases; C568343:MAN1B1 protein, human