Exon trapping/amplification was used to clone portions of genes from human chromosome 21. One trapped sequence showed complete homology with nucleotide sequence D13318 of GenBank, which corresponds to the gene for human transcription factor E4TF1-60 (HGMW-approved nomenclature GABPA). We mapped this gene to human chromosome 21 by FISH, somatic cell hybrids, and hybridization to chromosome 21-specific YACs. The GABPA gene localizes to YACs 816B7 and 848G1 of the Chumakov et al. (Nature 359: 380, 1992) YAC contig, near the APP gene in 21q21-q22.1. This transcription factor, which is an ETS-related DNA-binding protein and forms heterodimers with other polypeptides, may contribute in a gene dosage-dependent manner to the phenotype of Down syndrome.