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Science 9 December 1988:
Vol. 242. no. 4884, pp. 1409 - 1412
DOI: 10.1126/science.3264419
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Articles

Science, Vol 242, Issue 4884, 1409-1412
Copyright © 1988 by American Association for the Advancement of Science

articles

Neonatal hepatitis induced by alpha 1-antitrypsin: a transgenic mouse model

MJ Dycaico, SG Grant, K Felts, WS Nichols, SA Geller, JH Hager, AJ Pollard, SW Kohler, HP Short, FR Jirik, and al. et

Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048.

Transgenic mouse lineages were established that carry the normal (M) or mutant (Z) alleles of the human alpha 1-antitrypsin (alpha 1-Pi) gene. All of the alpha 1-Pi transgenic mice expressed the human protein in the liver, cartilage, gut, kidneys, lymphoid macrophages, and thymus. The human M-allele protein was secreted normally into the serum. However, the human Z-allele protein accumulated in several cell types, but particularly in hepatocytes, and was found in serum in tenfold lower concentrations than the M-allele protein. Mice in one lineage carrying the mutant Z allele expressed high levels of human alpha 1-Pi RNA and displayed significant runting (50% of normal weight) in the neonatal period. This lineage was found to have alpha 1-Pi-induced liver pathology in the neonatal period, concomitant with the accumulation of human Z protein in diastase-resistant cytoplasmic globules that could be revealed in the Periodic acid-Schiff reaction (PAS). The phenotype of mice in the strain expressing high levels of the Z allele is remarkably similar to human neonatal hepatitis, and this strain may prove to be a useful animal model for studying this disease.


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