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doi: 10.1242/10.1242/dev.00350

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Drosophila necrotic mutations mirror disease-associated variants of human serpins

Clare Green¹, Gemma Brown^1,*, Timothy R. Dafforn^2,, Jean-Marc Reichhart³, Terri Morley¹, David A. Lomas⁴ and David Gubb^1,

¹ Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
² Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK
³ UPR 9022 CNRS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France
⁴ Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK
^* Present address: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Present address: Biological Sciences, University of Manchester, 2.205 Stopford Building, Oxford Road, Manchester M13 9PT, UK

Author for correspondence (e-mail: d.gubb{at}gen.cam.ac.uk)

Accepted 18 December 2002

Polymerization of members of the serpin superfamily underlies diseases as diverse as cirrhosis, angioedema, thrombosis and dementia. The Drosophila serpin Necrotic controls the innate immune response and is homologous to human ₁-antitrypsin. We show that necrotic mutations that are identical to the Z-deficiency variant of ₁-antitrypsin form urea-stable polymers in vivo. These necrotic mutations are temperature sensitive, which is in keeping with the temperature-dependent polymerization of serpins in vitro and the role of childhood fevers in exacerbating liver disease in Z -antitrypsin deficiency. In addition, we identify two nec mutations homologous to an antithrombin point mutation that is responsible for neonatal thrombosis. Transgenic flies carrying an S>F amino-acid substitution equivalent to that found in Siiyama-variant antitrypsin (nec^S>F.UAS) fail to complement nec-null mutations and demonstrate a dominant temperature-dependent inactivation of the wild-type nec allele. Taken together, these data establish Drosophila as a powerful system to study serpin polymerization in vivo.

Key words: Necrotic, Serpin, Polymer, Z-variant ₁-antitrypsin, Conformational disease, Drosophila

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