Neonatal hepatitis induced by alpha 1-antitrypsin: a transgenic mouse model.
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.
Dycaico
M J
MJ
Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048.
Grant
S G
SG
Felts
K
K
Nichols
W S
WS
Geller
S A
SA
Hager
J H
JH
Pollard
A J
AJ
Kohler
S W
SW
Short
H P
HP
Jirik
F R
FR
D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005796:Genes; D006505:Hepatitis / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009154:Mutation; D000515:alpha 1-Antitrypsin / Q000235:genetics*
D000515:alpha 1-Antitrypsin