Heteropolymerization of S, I, and Z alpha(1)-antitrypsin and liver cirrhosis

The association between Z alpha(1)-antitrypsin deficiency and juvenile cirr hosis is well-recognized, and there is now convincing evidence that the hep atic inclusions are the result of entangled polymers of mutant Z alpha(1)-a ntitrypsin. Four percent of the northern European Caucasian population are heterozygotes for the Z variant, but even more common is S alpha(1)-antitry psin, which is found in up to 28% of southern Europeans. The S variant is k nown to have an increased susceptibility to polymerization, although this i s marginal compared with the more conformationally unstable Z variant. Ther e 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 alpha (1)-antitrypsin and another conformationally unstable variant (I alpha(1)-a ntitrypsin; (39)Arg-->Cys) identified in a 34-year-old man with cirrhosis r elated to al-antitrypsin deficiency. The conformational stability of the I variant has been characterized, and we have used fluorescence resonance ene rgy transfer to demonstrate the formation of heteropolymers between S and Z alpha(1)-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.