International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


POSTER 23 - QUANTITATIVE TRAIT LOCI MAPPING FOR LIVER FIBROSIS IN BALB/cJ AND A/J INBRED STRAINS OF MICE

Dr. Sonja Hillebrandt
Department of Medicine III
University of Technology (RWTH)
Pauwelsstrasse 30
52074 Aachen
Germany

Co-authors: Dr. Frank Lammert
Institutions: Department of Medicine III, University of Technology (RWTH)

Environmental factors are known to modulate hepatic fibrosis, but genes that determine progression of this disease are yet to be studied systematically. Our aim was to map responsible genes in an intercross between a susceptible and a resistant inbred mouse strain. Methods: To induce liver fibrosis, CCl4 was administrated to mice of seven inbred strains, to F1 hybrid mice of susceptible and resistant strains and to the F2 generation of those strains. Phenotypic characterisation of hepatic fibrosis included quantification of collagen in liver, determination of fibrosis markers in serum and liver histology. Intercross progeny with extreme phenotypes were genotyped at ~20 cM intervals to find the loci determining liver fibrosis. The segregation of marker alleles was calculated by MapManagerQT. Results: In the CCl4 mouse model, marked strain differences in susceptibility to fibrosis exist. Hepatic collagen contents in sensitive BALB/c mice are significantly higher compared to resistant strains FVB/N and A. Liver histology reveals periportal fibrosis in BALB/c mice and minimal changes in resistant strains. Identical phenotypes in F1 mice and resistant strains demonstrate that susceptibility to CCl4-induced hepatic fibrosis is a recessive trait. A linkage disequilibrium of the D2Mit113alleles was calculated. This marker maps near to MMP-9, a gene encoding a matrix metalloproteinase, which degrades matrix proteins during the fibrotic process. The set of inbred mouse strains used in this study provides an experimental framework for identification of novel fibrogenic genes by genome-wide scans.


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