Single-minded homolog 1 also known as class E basic helix-loop-helix protein 14 (bHLHe14) is a protein that in humans is encoded by the SIM1gene.[1][2][3]
SIM1 and SIM2 genes are homologs of Drosophila melanogaster single-minded (sim), so named because cells in the midline of the sim mutant embryo fail to properly develop and eventually die, and thus the paired longitudinal axon bundles that span the anterior-posterior axis of the embryo (analogous to the embryo's spinal cord) are collapsed into a "single" rudimentary axon bundle at the midline. Sim is a basic helix-loop-helix-PAS domaintranscription factor that regulates gene expression in the midline cells. Since the sim gene plays an important role in Drosophila development and has peak levels of expression during the period of neurogenesis, it was proposed that the human SIM2 gene, which resides in a critical region of chromosome 21, is a candidate for involvement in certain dysmorphic features (particularly facial and skull characteristics), abnormalities of brain development, and/or mental retardation of Down syndrome.[3]
Haploinsufficiency of SIM1 has been shown to cause severe early-onset obesity in a human girl with a de novo balanced translocation between chromosomes 1p22.1 and 6q16.2 [4] and has been suggested to cause a Prader-Willi-like phenotype in other cases.[5] Additionally, studies in mice have shown that haploinsufficieny of Sim1 causes obesity that is due to hyperphagia and do not respond properly to increased dietary fat.[2][6] Overexpression of SIM1 protects against diet induced obesity and rescues the hyperphagia of agouti yellow mice,[7] who have disrupted melanocortin signaling. The obesity and hyperphagia may be mediated by impaired melanocortin activation of PVN neurons [8] and oxytocin deficiency in these mice.[9] It has been demonstrated that modulating Sim1 levels postnatally also leads to hyperphagia and obesity,[10][11] suggesting a physiological role for Sim1 separate from its role in development.
↑ 2.02.1Michaud JL, Boucher F, Melnyk A, Gauthier F, Goshu E, Lévy E, Mitchell GA, Himms-Hagen J, Fan CM (Jul 2001). "Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus". Human Molecular Genetics. 10 (14): 1465–73. doi:10.1093/hmg/10.14.1465. PMID11448938.
↑Holder JL, Butte NF, Zinn AR (Jan 2000). "Profound obesity associated with a balanced translocation that disrupts the SIM1 gene". Human Molecular Genetics. 9 (1): 101–8. doi:10.1093/hmg/9.1.101. PMID10587584.
↑Holder JL, Zhang L, Kublaoui BM, DiLeone RJ, Oz OK, Bair CH, Lee YH, Zinn AR (Jul 2004). "Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice". American Journal of Physiology. Endocrinology and Metabolism. 287 (1): E105–13. doi:10.1152/ajpendo.00446.2003. PMID14982752.
↑Yang C, Gagnon D, Vachon P, Tremblay A, Levy E, Massie B, Michaud JL (Jun 2006). "Adenoviral-mediated modulation of Sim1 expression in the paraventricular nucleus affects food intake". The Journal of Neuroscience. 26 (26): 7116–20. doi:10.1523/JNEUROSCI.0672-06.2006. PMID16807340.
↑Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O (Feb 1997). "Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein". The Journal of Biological Chemistry. 272 (7): 4451–7. doi:10.1074/jbc.272.7.4451. PMID9020169.
↑Woods SL, Whitelaw ML (Mar 2002). "Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors". The Journal of Biological Chemistry. 277 (12): 10236–43. doi:10.1074/jbc.M110752200. PMID11782478.
Fan CM, Kuwana E, Bulfone A, Fletcher CF, Copeland NG, Jenkins NA, Crews S, Martinez S, Puelles L, Rubenstein JL, Tessier-Lavigne M (Jan 1996). "Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome". Molecular and Cellular Neurosciences. 7 (1): 1–16. doi:10.1006/mcne.1996.0001. PMID8812055.
Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O (Feb 1997). "Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein". The Journal of Biological Chemistry. 272 (7): 4451–7. doi:10.1074/jbc.272.7.4451. PMID9020169.
Holder JL, Butte NF, Zinn AR (Jan 2000). "Profound obesity associated with a balanced translocation that disrupts the SIM1 gene". Human Molecular Genetics. 9 (1): 101–8. doi:10.1093/hmg/9.1.101. PMID10587584.
Woods SL, Whitelaw ML (Mar 2002). "Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors". The Journal of Biological Chemistry. 277 (12): 10236–43. doi:10.1074/jbc.M110752200. PMID11782478.
Yamaki A, Kudoh J, Shimizu N, Shimizu Y (Jan 2004). "A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2". Biochemical and Biophysical Research Communications. 313 (3): 482–8. doi:10.1016/j.bbrc.2003.11.168. PMID14697214.
Meyre D, Lecoeur C, Delplanque J, Francke S, Vatin V, Durand E, Weill J, Dina C, Froguel P (Mar 2004). "A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2". Diabetes. 53 (3): 803–11. doi:10.2337/diabetes.53.3.803. PMID14988267.
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