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.[5][6][7]
Function
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. Because 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, or mental retardation of Down syndrome.[7]
Clinical significance
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[8] and has been suggested to cause a Prader-Willi-like phenotype in other cases.[9] Additionally, studies in mice have shown that haploinsufficiency of Sim1 causes obesity that is due to hyperphagia and do not respond properly to increased dietary fat.[6][10] Overexpression of SIM1 protects against diet induced obesity and rescues the hyperphagia of agouti yellow mice,[11] who have disrupted melanocortin signaling. The obesity and hyperphagia may be mediated by impaired melanocortin activation of PVN neurons[12] and oxytocin deficiency in these mice.[13] It has been demonstrated that modulating SIM1 levels postnatally also leads to hyperphagia and obesity,[14][15] suggesting a physiological role for SIM1 separate from its role in development.
^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.
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. S2CID11411254.
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.
