Figure 2

The Z-allele is the most important genetic defect in alpha-1-antitrypsin deficiency. It is a single mutation in exon 5 of the gene, leading to substitution of the amino acid glutamine (G) in position 342 in the protein for a lysine (A) amino acid. Alpha-1-antitrypsin is an important protease inhibitor, in particular of neutrophil elastase. The Z allele results in hepatic polymerization in both hepatocyte inclusions and decreased serum concentration. Therefore, strategies to augment the inherited deficiency as well as the development of small peptides that can selectively inhibit polymerization of the Z allele of the AAT protein in the liver are central to therapeutic approach.