title: The mammalian single-minded (SIM) gene: mouse cDNA structure and diencephalic expression indicate a candidate gene for Down syndrome.
abstract: We have recently isolated a human homolog (hSIM) of the Drosophila single-minded (sim) gene from the Down syndrome critical region of chromosome 21 using the exon trapping method. The Drosophila sim gene encodes a transcription factor that regulates the development of the central nervous system midline cell lineage. To elucidate the structure of the mammalian SIM protein, we have isolated cDNA clones from a mouse embryo cDNA library. The cDNA clones encode a polypeptide of 657 amino acids with a bHLH (basic-helix-loop-helix) domain, characteristic of a large family of transcription factors, and a PAS (Per-Arnt-Sim) domain in the amino-terminal half region. Both of these domains have striking sequence homology with human SIM and Drosophila SIM proteins. In contrast, the carboxy-terminal half of the mouse SIM protein consists of a proline-rich region with no sequence homology to the Drosophila SIM protein. A similar proline-rich domain is known for the activator domain of a number of transcription factors. Whole-mount embryo in situ hybridization experiments revealed that the SIM mRNA is expressed prominently in the diencephalon of mouse embryos at 8-9.5 days postcoitum. The structural characteristics of the mouse SIM protein and its expression in the diencephalon during embryogenesis strongly suggest that the newly isolated mammalian SIM homolog may play a critical role in the development of the mammalian central nervous system. We propose that the human SIM gene may be one of the pathogenic genes of Down syndrome.
authors.affiliation: Department of Molecular Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yamaki
authors.forename: S
authors.initials: S
authors.lastname: Noda
authors.forename: J
authors.initials: J
authors.lastname: Kudoh
authors.forename: N
authors.initials: N
authors.lastname: Shindoh
authors.forename: H
authors.initials: H
authors.lastname: Maeda
authors.forename: S
authors.initials: S
authors.lastname: Minoshima
authors.forename: K
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Shimizu
authors.forename: N
authors.initials: N
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D004027:Diencephalon / Q000196:embryology / Q000378:metabolism*; D004314:Down Syndrome / Q000235:genetics*; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics; D005326:Fetal Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D015723:Gene Library; D005796:Genes; D018257:Helix-Loop-Helix Motifs / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D008322:Mammals / Q000235:genetics; D051379:Mice / Q000235:genetics*; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D016366:Open Reading Frames; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005326:Fetal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C089449:sim protein, Drosophila