Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 603128

SIM bHLH TRANSCRIPTION FACTOR 1; SIM1

Alternative titles; symbols

SINGLE-MINDED, DROSOPHILA, HOMOLOG OF, 1

HGNC Approved Gene Symbol: SIM1

Cytogenetic location: 6q16.3 Genomic coordinates (GRCh38) : 6:100,385,009-100,464,921 (from NCBI)

TEXT

Description

SIM1 belongs to the bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) family of trnascription factors, which are characterized by an N-terminal bHLH domain required for DNA binding and dimerization and a PAS domain that acts as a secondary dimerization interface. Transcriptional control of target genes requires heterodimerization with another transcription factor, aryl-hydrocarbon receptor nuclear translocator (ARNT; 126110), or a homolog prevalent in the central nervous system, ARNT2 (606036) (summary by Ramachandrappa et al., 2013).

Cloning and Expression

Chrast et al. (1997) cloned human fetal kidney cDNAs corresponding to 2 homologs of the Drosophila sim gene, SIM1 and SIM2 (600892). SIM1 encodes a deduced protein with 766 amino acids and a calculated molecular mass of 85 kD. The human and mouse SIM1 proteins have 96% amino acid sequence identity. Human SIM1 shows 87.2% amino acid identity with SIM2 in its N-terminal half, which includes the conserved bHLH, PAS1, PAS2, and HST domains, and 18% identity in its C-terminal part, which contains a ser-rich region. Northern blot analysis of 20 human adult and fetal tissues detected an approximately 9.5-kb SIM1 transcript only in fetal kidney.

Mapping

By fluorescence in situ hybridization and radiation hybrid mapping, Chrast et al. (1997) localized the SIM1 gene to 6q16.3-q21. Fan et al. (1996) mapped the mouse Sim1 gene to the proximal region of chromosome 10, between Fyn (see 137025) and Ros1 (see 165020).

Gene Function

Holder et al. (2000) noted that mouse Sim1 is expressed in the developing kidney and central nervous system and is essential for formation of the supraoptic and paraventricular (PVN) nuclei of the hypothalamus. Previous neuroanatomic and pharmacologic studies have implicated the PVN in the regulation of body weight: PVN neurons express the melanocortin-4 receptor (MC4R; 155541) and appear to be physiologic targets of alpha-melanocyte-stimulating hormone (176830), which inhibits food intake.

Bonnefond et al. (2013) noted that one of the aryl hydrocarbon receptor nuclear translocators, either ARNT or ARNT2, is required as a dimerization partner for SIM1 to function as a transcription factor.

Cytogenetics

Studies of mice and humans have revealed a number of genes that when mutated result in severe obesity. Holder et al. (2000) studied a girl with early-onset obesity and a balanced translocation between 1p22.1 and 6q16.2. Holder et al. (2000) cloned and sequenced both translocation breakpoints. The translocation did not appear to affect any transcription unit on 1p, but it disrupted the SIM1 gene on 6q, separating the 5-prime promoter region and the bHLH domain from the 3-prime PAS and putative transcriptional regulation domains. Holder et al. (2000) hypothesized that haploinsufficiency of SIM1, possibly acting upstream or downstream of MC4R in the PVN, was responsible for severe obesity in their patient. In a boy with a Prader-Willi-syndrome (PWS; 176270)-like phenotype, including obesity, Faivre et al. (2002) identified a deletion of chromosome 6q16.1-q21, resulting in deletion of the SIM1 gene.

Animal Model

Mice homozygous for a null allele of Sim1 (Sim1 -/-) lack a paraventricular nucleus (PVN) and die perinatally. In contrast, Michaud et al. (2001) showed that Sim1 heterozygous mice were viable but developed early-onset obesity, with increased linear growth, hyperinsulinemia, and hyperleptinemia. Sim1 +/- mice were hyperphagic but their energy expenditure was not decreased, distinguishing them from other mouse models of early-onset obesity such as deficiencies in leptin (164160) and melanocortin receptor-4 (155541). Quantitative histologic comparison with normal littermates showed that the PVN of Sim1 +/- mice contains on average 24% fewer cells without a selective loss of any identifiable major cell type. Since acquired lesions in the PVN also induce increased appetite without a decrease in energy expenditure, the authors proposed that abnormalities of PVN development may cause the obesity of Sim1 +/- mice.

REFERENCES

  1. Bonnefond, A., Raimondo, A., Stutzmann, F., Ghoussaini, M., Ramachandrappa, S., Bersten, D. C., Durand, E., Vatin, V., Balkau, B., Lantieri, O., Raverdy, V., Pattou, F., and 12 others.Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features. J. Clin. Invest. 123: 3037-3041, 2013. [PubMed: 23778136] [Full Text: https://doi.org/10.1172/JCI68035\]
  2. Chrast, R., Scott, H. S., Chen, H., Kudoh, J., Rossier, C., Minoshima, S., Wang, Y., Shimizu, N., Antonarakis, S. E.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. Genome Res. 7: 615-624, 1997. [PubMed: 9199934] [Full Text: https://doi.org/10.1101/gr.7.6.615\]
  3. Faivre, L., Cormier-Daire, V., Lapierre, J. M., Colleaux, L., Jacquemont, S., Genevieve, D., Saunier, P., Munnich, A., Turleau, C., Romana, S., Prieur, M., de Blois, M. C., Vekemans, M.Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype. (Letter) J. Med. Genet. 39: 594-596, 2002. Note: Erratum: J. Med. Genet. 41: 320 only, 2004. [PubMed: 12161602] [Full Text: https://doi.org/10.1136/jmg.39.8.594\]
  4. Fan, C. M., Kuwana, E., Bulfone, A., Fletcher, C. F., Copeland, N. G., Jenkins, N. A., Crews, S., Martinez, S., Puelles, L., Rubenstein, J. L., Tessier-Lavigne, M.Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome. Molec. Cell. Neurosci. 7: 1-16, 1996. Note: Erratum: Molec. Cell. Neurosci. 7: 519 only, 1996. [PubMed: 8812055] [Full Text: https://doi.org/10.1006/mcne.1996.0001\]
  5. Holder, J. L., Jr., Butte, N. F., Zinn, A. R.Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum. Molec. Genet. 9: 101-108, 2000. [PubMed: 10587584] [Full Text: https://doi.org/10.1093/hmg/9.1.101\]
  6. Michaud, J. L., Boucher, F., Melnyk, A., Gauthier, F., Goshu, E., Levy, E., Mitchell, G. A., Himms-Hagen, J., Fan, C.-M.Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum. Molec. Genet. 10: 1465-1473, 2001. [PubMed: 11448938] [Full Text: https://doi.org/10.1093/hmg/10.14.1465\]
  7. Ramachandrappa, S., Raimondo, A., Cali, A. M. G., Keogh, J. M. Henning, E., Saeed, S., thompson, A., Garg, S., Bochukova, E. G., Brage, S., Trowse, V., Wheeler, E., and 11 others.Rare variants in single-minded 1 (SIM1) are associated with severe obesity. J. Clin. Invest. 123: 3042-3050, 2013. Note: Erratum: J. Clin. Invest. 123: 3635 only, 2013. [PubMed: 23778139] [Full Text: https://doi.org/10.1172/JCI68016\]

Contributors:

Carol A. Bocchini - updated : 05/19/2016
Cassandra L. Kniffin - updated : 11/14/2003
George E. Tiller - updated : 12/7/2001
Victor A. McKusick - updated : 2/16/2000

Creation Date:

Sheryl A. Jankowski : 10/13/1998

Edit History:

carol : 04/15/2020
carol : 04/14/2020
carol : 05/19/2016
terry : 3/14/2013
terry : 10/10/2012
carol : 11/17/2003
ckniffin : 11/14/2003
cwells : 12/18/2001
cwells : 12/7/2001
mgross : 3/9/2000
terry : 2/16/2000
psherman : 10/14/1998
psherman : 10/13/1998
psherman : 10/13/1998