DEVELOPMENT AND DISEASE Drosophila necrotic mutations mirror disease-associated variants of human serpins

The serpin (serine proteinase inhibitor) superfamily includes antithrombin, α1-antitrypsin and PAI-1, which control the coagulation, inflammation and fibrinolytic pathways, respectively. Serpins have a unique method of inhibition that involves a conformational change of the protein (Huntington et al., 2000). This transition is essential for the mechanism of serpin inhibition but it renders serpins susceptible to mutations that affect conformational stability (Carrell and Lomas, 2002) and lead to polymer formation (Lomas et al., 1992; Dafforn et al., 1999; Huntington et al., 1999; Sivasothy et al., 2000). The most well characterized of these conditions is deficiency of the human serpin α1-antitrypsin. α1-Antitrypsin is synthesized in the liver and is the most abundant circulating proteinase inhibitor in humans. Most individuals carry the normal M allele but 1 in 25 northern Europeans are heterozygous for the Z variant (Blanco et al., 2001). The Z mutation (Glu342→Lys) favors the spontaneous formation of polymers between the reactive center loop of one molecule and β-sheet A of another (Lomas et al., 1992; Dafforn et al., 1999; Sivasothy et al., 2000). These polymers are retained within hepatocytes to form inclusion bodies that are associated with neonatal hepatitis (Sveger, 1976), cirrhosis (Sveger, 1988) and hepatocellular carcinoma (Eriksson et al., 1986). In addition, the lack of circulating α1-antitrypsin predisposes to early-onset emphysema, by failing to protect the lungs against proteolytic attack (Eriksson, 1965). Thus, α1antitrypsin deficiency results in two clear phenotypes. The toxic effect of polymer accumulation causes cirrhosis while the consequent lack of inhibitory activity results in emphysema. Polymerization also underlies deficiency of antithrombin, C1-inhibitor and α1-antichymotrypsin, which are associated with thrombosis (Bruce et al., 1994), angio-edema (Aulak et al., 1993; Eldering et al., 1995) and emphysema (Gooptu et al., 2000), respectively, and the accumulation of mutant neuroserpin protein within the brain, which causes an inclusion body dementia (Davis et al., 1999; Belorgey et al., 2002). 1473 Development 130, 1473-1478 © 2003 The Company of Biologists Ltd doi:10.1242/dev.00350