OVEREXPRESSION OF LIVER-TYPE PHOSPHOFRUCTOKINASE (PFKL) IN TRANSGENIC-PFKL MICE - IMPLICATION FOR GENE DOSAGE IN TRISOMY-21

The human liver-type subunit of the key glycolytic enzyme, phosphofruc tokinase (PFKL), is encoded by a gene residing on chromosome 21. This chromosome, when triplicated, causes the phenotypic expression of Down 's syndrome (trisomy 21). Increased phosphofructokinase activity, a re sult of gene dosage, is commonly found in erythrocytes and fibroblasts from Down's syndrome patients. We describe the construction of transg enic mice overexpressing PFKL for use as a well-defined model system, in which the effects of PFKL overexpression in various tissues, and th roughout development, can be studied. Mice transgenic for a murine PFK L 'gene cDNA' hybrid construct were found to overexpress PFKL in a tis sue-specific manner resembling that of the endogenous enzyme. Although unchanged in adult brain, PFK specific activity was found to have bee n almost doubled in brains of embryonic transgenic-PFKL mice, suggesti ng that the extra copies of the PFKL gene are expressed during the dev elopmental period. This pattern of overexpression of PFKL in brains of transgenic-PFKL mice suggests that gene-dosage effects may be tempora lly separated from some of their consequences, adding an additional la yer of complexity to the analysis of gene dosage in trisomy 21.