Using a modified Tag & Exchange targeting scheme, the Hprt minigene in the tagged Fgf2 knock-out allele (Zhou et al, Nature Medicine, 4:201, 1998) was "exchanged" by gene targeting with a 14 bp oligonucleotide designed to produce stop codons in all three reading frames and to cause a frameshift in translation products originating from the noncanonical CTG initiation codon. Cells with the exchanged allele were selected for the loss of HPRT function using 6-thioguanine. The loss of high molecular weight protein product expression was confirmed by western blot analysis on heart, liver and brain extracts. The low molecular weight protein product is still expressed. (J:144353)