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The association between Z [small alpha, Greek]1-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 [small alpha, Greek]1-antitrypsin. Four percent of the northern European Caucasian population are heterozygotes for the Z variant, but even more common is S [small alpha, Greek] (1-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 [small alpha, Greek]1-antitrypsin and another conformationally unstable variant (I [small alpha, Greek]1-antitrypsin; (39) Arg[rightward arrow]Cys) identified in a 34-year-old man with cirrhosis related to [small alpha, Greek]1-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 [small alpha, Greek]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.J.Clin. Invest. 103:999-1006 (1999).