We have isolated two novel genes, designated DSCR5 and DSCR6, from the Down syndrome critical region (DSCR) on chromosome 21q22.2 which has been defined as minimal overlapping region of partial trisomy 21 patients and located between t(4;21) break point and ERG (approximately 1.6 Mb), DSCR5 and DSCR6 genes consist of 6 and 5 exons, respectively. Alternative use of transcription start sites and alternative splicing events produce different RNA species and proteins from both genes, Three different transcripts of DSCR5 gene encode three putative transmembrane proteins of 158, 134, and 108 amino acids, while 4 different transcripts of DSCR6 gene encode two forms of proteins with 190 and 106 amino acids. The DSCR5 gene is expressed in various human tissues examined, whereas the DSCR6 gene is expressed only in limited tissues at low level. Both DSCR5 and DSCR6 genes are candidates for the pathogenesis of Down syndrome, although the function of these genes remains to be elucidated.