A transgenic zebrafish model of hepatocyte function in human Z α1-antitrypsin deficiency

In human alpha 1-antitrypsin deficiency, homozygous carriers of the Z (E324K) mutation in the gene SERPINA1 have insufficient circulating alpha 1-antitrypsin and are predisposed to emphysema. Misfolding and accumulation of the mutant protein in hepatocytes also causes endoplasmic reticulum stress and underpins long-term liver damage. Here, we describe transgenic zebrafish (Danio rerio) expressing the wildtype or the Z mutant form of human alpha 1-antitrypsin in hepatocytes. As observed in afflicted humans, and in rodent models, about 80% less alpha 1-antitrypsin is evident in the circulation of zebrafish expressing the Z mutant. Although these zebrafish also show signs of liver stress, they do not accumulate alpha 1-antitrypsin in hepatocytes. This new zebrafish model will provide useful insights into understanding and treatment of alpha 1-antitrypsin deficiency.