Repair of the secretion defect in the Z form of alpha 1-antitrypsin by addition of a second mutation. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cell Line
  • Codon
  • DNA
  • Electrochemistry
  • Endoplasmic Reticulum
  • Glutamates
  • Glutamic Acid
  • Humans
  • Lysine
  • Protein Conformation
  • RNA, Messenger
  • Structure-Activity Relationship
  • Transfection
  • alpha 1-Antitrypsin Deficiency

MeSH Major

  • Mutation
  • alpha 1-Antitrypsin

abstract

  • Homozygous inheritance of the Z-type mutant form of the alpha 1-antitrypsin (alpha 1AT) gene results in the most common form of alpha 1AT deficiency, a human hereditary disease associated with a high risk for the development of emphysema and an increased incidence of neonatal hepatitis. The alpha 1AT-synthesizing cells of individuals with the Z gene have normal alpha 1AT messenger RNA levels, but alpha 1AT secretion is markedly reduced secondary to accumulation of newly synthesized alpha 1AT in the rough endoplasmic reticulum. Crystallographic analysis of alpha 1AT predicts that in normal alpha 1AT, a negatively charged Glu342 is adjacent to positively charged Lys290. Thus the Glu342----Lys342 Z mutation caused the loss of a normal salt bridge, resulting in the intracellular aggregation of the Z molecule. The prediction was made that a second mutation in the alpha 1AT genet that changed the positively charged Lys290 to a negatively charged Glu290 would correct the secretion defect. When the second mutation was added to the Z-type complementary DNA, the resulting gene directed the synthesis and secretion of amounts of alpha 1AT similar to that directed by the normal alpha 1AT complementary DNA in an in vitro eukaryotic expression system. This suggests the possibility that a human hereditary disease can be corrected by inserting an additional mutation in the same gene.

publication date

  • December 23, 1988

has subject area

  • Animals
  • Cell Line
  • Codon
  • DNA
  • Electrochemistry
  • Endoplasmic Reticulum
  • Glutamates
  • Glutamic Acid
  • Humans
  • Lysine
  • Mutation
  • Protein Conformation
  • RNA, Messenger
  • Structure-Activity Relationship
  • Transfection
  • alpha 1-Antitrypsin
  • alpha 1-Antitrypsin Deficiency

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed ID

  • 2904702

Additional Document Info

start page

  • 1700

end page

  • 1702

volume

  • 242

number

  • 4886