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.