Variable Expression of Hepatic Glucokinase in Mice Is Due to a Regulational Locus That Cosegregates with the Glucokinase Gene

TheGk activitylocus affects expression of hepatic glucokinase (GK) in mice. Analysis of microsatellites within the mouse GK gene locus revealed two major haplotypes in 19 of 22 inbred strains predictive of either high or low hepatic GK gene expression. C3H/HeJ mice, a high-activity strain, and two other wild-derived strains contain less common haplotypes. No coding sequence differences were found in hepatic GK-coding sequences from representative high and lowGk activitystrains, thereby excluding kinetic abnormalities as the basis for hepatic GK activity differences. Screening of ∼10 kb of potential regulatory DNA, including all eight known and three of four newly identified DNase I-hypersensitive sites, by restriction enzyme fingerprinting–single-strand conformation analysis revealed a tetranucleotide microsatellite, the length of which was also predictive of theGk activityphenotype. This tetranucleotide repeat is located in the first intron of the hepatic transcription unit and lies close to a newly identified liver-specific DNase I-hypersensitive site. These results indicate that theGk activityalleles are a regulational locus associated with the GK gene locus.