Cloning of Two Human Homologs of the Drosophila single-minded Gene SIM1 on Chromosome 6q and SIM2 on 21q Within the Down Syndrome Chromosomal Region Roman Chrast, 1,2 Hamish S. Scott, 1 Haiming Chen, 1 Jun Kudoh, 4 Colette Rossier, 1 Shinsei Minoshima, 4 Yimin Wang, 4 Nobuyoshi Shimizu, 4 and Stylianos E. Antonarakis 1,2,3,5 1 Laboratory of Human Molecular Genetics, Department of Genetics and Microbiology and 2 Graduate Program of Cellular and Molecular Biology, Geneva University Medical School, 1211 Geneva, Switzerland; 3 Division of Medical Genetics, Cantonal Hospital of Geneva, 1211 Geneva, Switzerland; 4 Department of Molecular Biology, Keio University School of Medicine, Tokyo 160, Japan As part of our effort to clone genes of human chromosome 21 that may contribute to Down syndrome, we have previously isolated four exons with homology to Drosophila single-minded (sim) gene, which encodes a transcription factor that is a master regulator of fruit fly neurogenesis. These exons were used to clone and characterize two human homologs of the Drosophila sim gene, SIM1 and SIM2, which map to chromosomes 6q16.3–q21 and 21q22.2, respectively; SIM2 maps within the so-called Down syndrome chromosomal region. Recently, two mouse homologs, Sim1 and Sim2, also have been identified. There is a high level of homology among human, mouse, and Drosophila sim genes in their amino-terminal half where the conserved bHLH, PAS1, PAS2, and HST domains are present. In contrast, the carboxy-terminal parts are only homologous between SIM1 and Sim1 and SIM2 and Sim2. Two isoforms (SIM2 and SIM2s) of human SIM2 have been detected that differ in their 38 ends. Northern blot analysis revealed one mRNA SIM1 species of ∼9.5 kb and four different mRNA SIM2 species of 2.7, 3, 4.4, and 6 kb in human fetal kidney. The function of both human SIM1 and SIM2 is unknown. However, three copies of SIM2 may contribute to some specific Down syndrome phenotypes because of (1) mapping position, (2) potential function as transcriptional repressor, (3) likely dimerization with other transcription factors, (4) the temporal and spatial expression pattern of mouse Sim2, and (5) the potentially analogous role of human SIM2 to that of Drosophila sim during neurogenesis. [The sequence data described in this paper have been submitted to GenBank under accession nos. U70212, U80456, U80457, and AB003185.] Down syndrome (DS) is the most common autoso- mal aneuploidy occurring in 1.03 to 1.30 of 1000 live births (Epstein 1995). It is caused by the pres- ence of three copies of human chromosome 21 (HC21). A minimum region of HC21 [Down syn- drome chromosomal region (DSCR)] that in tripli- cation is associated with many phenotypic charac- teristics of DS has been defined between D21S17 and ETS2 (McCormick et al. 1989; Delabar et al. 1993). The DSCR concept was challenged as some patients with DS phenotypes have triplicated re- gions of HC21 proximal to this DSCR (Korenberg et al. 1994). However, the majority of partial trisomy 21 DS patients have three copies of the DSCR. To identify genes that contribute to phenotypes of DS, we have performed exon trapping (Chen et al. 1996) on HC21 cosmids and identified a human homolog of the Drosophila single-minded gene (sim) that maps within the DSCR on HC21 (Chen et al. 1995). This localization subsequently was con- firmed by others (Dahmane et al. 1995; Osoegawa et al. 1996). The Drosophila sim gene is the master regulator of fruit fly neurogenesis (Thomas et al. 1988; Nambu et al. 1991). Sim protein is a transcription 5 Corresponding author. E-MAIL sea@medsun.unige.ch; FAX 41 22 702 57 06. LETTER 7:615–624 ©1997 by Cold Spring Harbor Laboratory Press ISSN 1054-9803/97 $5.00 GENOME RESEARCH 615 Cold Spring Harbor Laboratory Press on January 24, 2022 - Published by genome.cshlp.org Downloaded from