Identification of an ENU mutant mouse with liver fibrosis

Abstract

With the human genome sequenced, the race is on to understand the functions of the 30,000 or so genes. Ethyl‐nitrosourea (ENU) was used to treat C57BL/6 (B6) male mice, followed by a 3‐generation breeding scheme to generate G3 mice that were screened for immunological phenotypes under recessive genetic control. The primary phenotype of one mutant, P321, was elevated serum AST/ALT. Major organs of affected mice were subjected to pathology analysis and striking liver‐specific fibrosis was found. Recessive mode of inheritance was confirmed by mating an affected G3 male to wildtype B6 females to generate F2 offspring. No affected phenotype was found in F1 mice and approximately 1 in 4 F2 mice were pheno‐deviants, consistent with monogenic control. Affected G3 mice were outcrossed to generated F2 offspring and the affected F2 mice were subjected to linkage analysis by haplotype interval mapping (Neuhaus and Beier, 1998. Mammalian Genome 9, 150‐154). The mutant gene was found to be linked to chromosome 5. The P‐321 mutant may be used as a model to study the molecular mechanism of liver fibrosis and to establish ways to treat, prevent, or delay the onset of such diseases.