Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis

J Clin Invest. 1999 Apr;103(7):999-1006. doi: 10.1172/JCI4874.

Abstract

The association between Z alpha1-antitrypsin deficiency and juvenile cirrhosis is well-recognized, and there is now convincing evidence that the hepatic inclusions are the result of entangled polymers of mutant Z alpha1-antitrypsin. Four percent of the northern European Caucasian population are heterozygotes for the Z variant, but even more common is S alpha1-antitrypsin, which is found in up to 28% of southern Europeans. The S variant is known to have an increased susceptibility to polymerization, although this is marginal compared with the more conformationally unstable Z variant. There has been speculation that the two may interact to produce cirrhosis, but this has never been demonstrated experimentally. This hypothesis was raised again by the observation reported here of a mixed heterozygote for Z alpha1-antitrypsin and another conformationally unstable variant (I alpha1-antitrypsin; 39Arg-->Cys) identified in a 34-year-old man with cirrhosis related to alpha1-antitrypsin deficiency. The conformational stability of the I variant has been characterized, and we have used fluorescence resonance energy transfer to demonstrate the formation of heteropolymers between S and Z alpha1-antitrypsin. Taken together, these results indicate that not only may mixed variants form heteropolymers, but that this can causally lead to the development of cirrhosis.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • European Continental Ancestry Group
  • Heterozygote
  • Humans
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / pathology
  • Male
  • Microinjections
  • Models, Molecular
  • Mutation
  • Oocytes
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • RNA, Messenger / genetics
  • Xenopus
  • alpha 1-Antitrypsin / chemistry*
  • alpha 1-Antitrypsin Deficiency / genetics*

Substances

  • RNA, Messenger
  • alpha 1-Antitrypsin