VARIABLE EXPRESSION OF HEPATIC GLUCOKINASE IN MICE IS DUE TO A REGULATIONAL LOCUS THAT COSEGREGATES WITH THE GLUCOKINASE GENE

The Gk activity locus affects expression of hepatic glucokinase (GK) i n mice. Analysis of microsatellites within the mouse GK gene locus rev ealed two major haplotypes in 19 of 22 inbred strains predictive of ei ther high or low hepatic GK gene expression. C3H/HeJ mice, a high-acti vity strain, and two other wild-derived strains contain less common ha plotypes. No coding sequence differences were found in hepatic GK-codi ng sequences from representative high and low Gk activity strains, the reby excluding kinetic abnormalities as the basis for hepatic GK activ ity differences. Screening of similar to 10 kb of potential regulatory DNA, including all eight known and three of four newly identified DNa se I-hypersensitive sites, by restriction enzyme fingerprinting-single -strand conformation analysis revealed a tetranucleotide microsatellit e, the length of which was also predictive of the Gh activity phenotyp e. This tetranucleotide repeat is located in the first intron of the h epatic transcription unit and lies close to a newly identified liver-s pecific DNase I-hypersensitive site. These results indicate that the G k activity alleles are a regulational locus associated with the GK gen e locus. (C) 1997 Academic Press.