Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis
Ravi Mahadeva, … , Derek G.D. Wight, David A. Lomas
Ravi Mahadeva, … , Derek G.D. Wight, David A. Lomas
Published April 1, 1999
Citation Information: J Clin Invest. 1999;103(7):999-1006. https://doi.org/10.1172/JCI4874.
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Article

Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis

Abstract

The association between Z α1-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 α1-antitrypsin. Four percent of the northern European Caucasian population are heterozygotes for the Z variant, but even more common is S α1-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 α1-antitrypsin and another conformationally unstable variant (I α1-antitrypsin; 39Arg→Cys) identified in a 34-year-old man with cirrhosis related to α1-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 α1-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.

Authors

Ravi Mahadeva, Wun-Shaing W. Chang, Timothy R. Dafforn, Diana J. Oakley, Richard C. Foreman, Jacqueline Calvin, Derek G.D. Wight, David A. Lomas

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Figure 3

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Nondenaturing PAGE (7.5–15% wt/vol) showing that I α1-antitrypsin polyme...
Nondenaturing PAGE (7.5–15% wt/vol) showing that I α1-antitrypsin polymerized more readily than M α1-antitrypsin after incubation at 37°C at 2 mg/ml in 50 mM Tris, 50 mM KCl (pH 7.4). All lanes contain 10 μg protein. (a) M α1-antitrypsin 0 days, 2 days, 3 days, 6 days, and 12 days at 37°C. (c) I α1-antitrypsin 0 days, 2 days, 3 days, 6 days, and 12 days at 37°C. The electron micrograph of M (b) and I (d) α1-antitrypsin incubated at 2 mg/ml and 37°C for 12 days confirmed that I α1-antitrypsin formed chains of polymers, but M α1-antitrypsin remained monomeric when incubated under identical conditions. The electron micrographs were stained with 1% wt/vol uranyl acetate. Scale bar: 100 nm.