Alternative titles; symbols
HGNC Approved Gene Symbol: SIM2
Cytogenetic location: 21q22.13 Genomic coordinates (GRCh38): 21:36,699,115-36,749,917 (from NCBI)
In an effort to create a transcription map of chromosome 21 and to characterize genes that contribute to the etiology and pathophysiology of Down syndrome (DS; 190685), Chen et al. (1995) used exon trapping. Several trapped exons showed significant predicted amino acid homology to the Drosophila 'single-minded' (sim) gene, a master regulator of the early development of the fly central nervous system midline. Since the sim gene plays an important role in Drosophila development and has peak levels of expression during the period of neurogenesis, Chen et al. (1995) proposed that the human SIM gene is a candidate for involvement in certain dysmorphic features (particularly the facial and skull characteristics), abnormalities of brain development, and/or mental retardation of Down syndrome. They stated that no other gene product with involvement either in the development of the nervous or other system or in the regulation of gene expression had been identified and mapped in the Down syndrome critical region (DSCR, or DCR).
The Drosophila sim gene encodes a basic helix-loop-helix (bHLH) protein that is a transcription factor involved in CNS midline development. Muenke et al. (1995) noted that in mouse, 2 homologs of the sim gene have been identified, Sim1 and Sim2. Expression of Sim2 in the CNS is in the forebrain/midbrain region, the ventral-caudal portion of the diencephalon, and the rostral and caudal portions of the hypothalamus, regions potentially involved in HPE. Sim1 has a lower level of expression in the forebrain/midbrain region than does Sim2 but is otherwise expressed in a pattern similar to that of Sim2.
Dahmane et al. (1995) noted that many features of Down syndrome might result from the overdosage of only a few genes located in the DCR around the 21q22.2 subband. To search for these genes, cosmids mapping to this region were isolated by Dahmane et al. (1995) and used for trapping exons. One of the trapped exons obtained had a sequence similar to part of the Drosophila sim gene. Mapping data indicated that this exonic sequence is present only in the DCR in the human genome. Hybridization of this exonic sequence with human fetal kidney polyadenylated RNA revealed 2 transcripts of 6 and 4.3 kb. In situ hybridization of a probe derived from this exon with human and rat fetuses showed that the corresponding gene is expressed during early fetal life in the central nervous system and in other tissues, including the facial, skeletal, palate, and vertebra primordia. The expression pattern of this gene suggested to the authors that it may be involved in the pathogenesis of some of the morphologic features and brain anomalies of Down syndrome.
Yamaki et al. (1996) isolated a Sim cDNA (most likely Sim2) from a mouse embryo library. The predicted 675-amino acid protein contains both a bHLH domain and a PAS (Per-Arnt-Sim) domain as are found in the human and Drosophila SIM proteins. A proline-rich region, similar to that of the activator domain of several transcription factors, is present in the C-terminal portion of the protein. In situ hybridization showed expression in the diencephalon of 8- to 9.5-day mouse embryos. The same cDNA was reported by Moffett et al. (1996), who noted that the mouse and Drosophila proteins share 88% of residues within the bHLH domain. They designated the mouse gene 'msim.' Northern blots showed a 4-kb transcript expressed at highest levels in the kidney and in situ hybridization demonstrated early fetal expression in the central nervous system and in cartilage primordia.
DeYoung et al. (2003) determined that a colon-specific gene in the Cancer Genome Anatomy Project (CGAP) showed high homology with SIM2. They monitored SIM2 expression in solid tumors and found isoform-specific expression of SIM2 short-form (SIM2-s) selectively in colon, prostate, and pancreatic carcinomas but not in breast, lung, or ovarian carcinomas or in most normal tissues. In colon tumors, SIM2-s expression was seen in early stages. Antisense inhibition of SIM2-s expression in a colon cancer cell line caused inhibition of gene expression, growth inhibition, and apoptosis. The administration of the antisense, but not the control, oligonucleotides caused a pronounced inhibition of tumor growth in nude mice with no major toxicity. The findings provided a rationale for the genes-to-drugs paradigm and established SIM2-s as a molecular target for cancer therapeutics.
By hybridization to chromosome 21 YACs, Chen et al. (1995) assigned the SIM2 gene to chromosome 21q22.2, between markers D21S333 and D21S335.
Muenke et al. (1995) mapped the human SIM2 gene to chromosome 21q22.2-q22.3 by analysis of a somatic cell hybrid mapping panel. Since this gene could be involved in the chromosome 21 type of holoprosencephaly (236100), Muenke et al. (1995) analyzed somatic cell hybrids derived from HPE patients with deletion in chromosome 21 and showed that 2 of 3 patients did not have deletion of SIM2, thus ruling it out as a candidate for HPE1. On the other hand, SIM2 maps within the DCR and may contribute to the Down syndrome phenotype.
Ema et al. (1999) found that mouse Sim2 mRNA is expressed in hippocampus and amygdala of adult mice, and that while mice overexpressing Sim2 under the control of the beta-actin promoter are viable and fertile and have superficially normal skeletal, brain, and heart structures, they exhibit a moderate defect in context-dependent fear conditioning and a mild defect in the Morris water maze test. Taken together, the data showed that overdosage of Sim2 may be important for the pathogenesis of Down syndrome, especially mental retardation.
Chrast et al. (2000) created a bacterial artificial chromosome transgenic mice with 1 or 2 additional copies of mouse Sim2. The transgene was expressed in the same spatial pattern as the endogenous gene. The mice developed normally, were fertile, and did not show detectable histopathologic abnormalities. However, detailed analysis of their behavior revealed anxiety-related/reduced exploratory behavior and sensitivity to pain, phenotypes similar to those also present in other partial trisomy 16 mouse models of DS. The authors suggested that overexpression of SIM2 may contribute to the DS behavioral phenotype.
Goshu et al. (2002) found that Sim2-null mice died within 3 days of birth due to lung atelectasis and breathing failure. Diminished lung inflation appeared to be due to compromised structural components surrounding the pleural cavity, which included rib protrusions, abnormal intercostal muscle attachments, diaphragm hypoplasia, and pleural mesothelium tearing. Although each structure was minimally affected, the authors proposed that the combined effects led to mechanical failure of lung inflation and death. Sim2 mutants also developed scoliosis, reflected by the unequal sizes of the left and right vertebrae and ribs. Despite its overlapping expression with Sim1 in the paraventricular nucleus (PVN), Sim2 function appeared dispensable for PVN development.
Chen, H., Chrast, R., Rossier, C., Gos, A., Antonarakis, S. E., Kudoh, J., Yamaki, A., Shindoh, N., Maeda, H., Minoshima, S., Shimizu, N. Single-minded and Down syndrome? (Letter) Nature Genet. 10: 9-10, 1995. [PubMed: 7647800] [Full Text: https://doi.org/10.1038/ng0595-9]
Chrast, R., Scott, H. S., Madani, R., Huber, L., Wolfer, D. P., Prinz, M., Aguzzi, A., Lipp, H.-P., Antonarakis, S. E. Mice trisomic for a bacterial artificial chromosome with the single-minded 2 gene (Sim2) show phenotypes similar to some of those present in the partial trisomy 16 mouse models of Down syndrome. Hum. Molec. Genet. 9: 1853-1864, 2000. [PubMed: 10915774] [Full Text: https://doi.org/10.1093/hmg/9.12.1853]
Dahmane, N., Charron, G., Lopes, C., Yaspo, M.-L., Maunoury, C., Decorte, L., Sinet, P.-M., Bloch, B., Delabar, J.-M. Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development. Proc. Nat. Acad. Sci. 92: 9191-9195, 1995. [PubMed: 7568099] [Full Text: https://doi.org/10.1073/pnas.92.20.9191]
DeYoung, M. P., Tress, M., Narayanan, R. Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors. Proc. Nat. Acad. Sci. 100: 4760-4765, 2003. [PubMed: 12676991] [Full Text: https://doi.org/10.1073/pnas.0831000100]
Ema, M., Ikegami, S., Hosoya, T., Mimura, J., Ohtani, H., Nakao, K., Inokuchi, K., Katsuki, M., Fujii-Kuriyama, Y. Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome. Hum. Molec. Genet. 8: 1409-1415, 1999. [PubMed: 10400987] [Full Text: https://doi.org/10.1093/hmg/8.8.1409]
Goshu, E., Jin, H., Fasnacht, R., Sepenski, M., Michaud, J. L., Fan, C.-M. Sim2 mutants have developmental defects not overlapping with those of Sim1 mutants. Molec. Cell. Biol. 22: 4147-4157, 2002. [PubMed: 12024028] [Full Text: https://doi.org/10.1128/MCB.22.12.4147-4157.2002]
Moffett, P., Dayo, M., Reece, M., McCormick, M. K., Pelletier, J. Characterization of msim, a murine homologue of the Drosophila sim transcription factor. Genomics 35: 144-155, 1996. [PubMed: 8661115] [Full Text: https://doi.org/10.1006/geno.1996.0333]
Muenke, M., Bone, L. J., Mitchell, H. F., Hart, I., Walton, K., Hall-Johnson, K., Ippel, E. F., Dietz-Band, J., Kvaloy, K., Fan, C.-M., Tessier-Lavigne, M., Patterson, D. Physical mapping of the holoprosencephaly critical region in 21q22.3, exclusion of SIM2 as a candidate gene for holoprosencephaly, and mapping of SIM2 to a region of chromosome 21 important for Down syndrome. Am. J. Hum. Genet. 57: 1074-1079, 1995. [PubMed: 7485157]
Yamaki, A., Noda, S., Kudoh, J., Shindoh, N., Maeda, H., Minoshima, S., Kawasaki, K., Shimizu, Y., Shimizu, N. The mammalian single-minded (SIM) gene: mouse cDNA structure and diencephalic expression indicate a candidate gene for Down syndrome. Genomics 35: 136-143, 1996. [PubMed: 8661114] [Full Text: https://doi.org/10.1006/geno.1996.0332]