SIM1

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Species	Human	Mouse
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Wikidata
View/Edit Human

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 SIM1 gene.

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 domain transcription 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.

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 and has been suggested to cause a Prader-Willi-like phenotype in other cases. 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. Overexpression of SIM1 protects against diet induced obesity and rescues the hyperphagia of agouti yellow mice, who have disrupted melanocortin signaling. The obesity and hyperphagia may be mediated by impaired melanocortin activation of PVN neurons and oxytocin deficiency in these mice. It has been demonstrated that modulating Sim1 levels postnatally also leads to hyperphagia and obesity, suggesting a physiological role for Sim1 separate from its role in development.

Interactions

SIM1 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator.

Further reading

• 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. PMID 8812055.
• 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. PMID 9020169.
• 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. PMID 10587584.
• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• 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. PMID 11782478.
• Faivre L, Cormier-Daire V, Lapierre JM, Colleaux L, Jacquemont S, Geneviéve D, Saunier P, Munnich A, Turleau C, Romana S, Prieur M, De Blois MC, Vekemans M (Aug 2002). "Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype". Journal of Medical Genetics. 39 (8): 594–6. doi:10.1136/jmg.39.8.594. PMC 1735217. PMID 12161602.
• 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. PMID 14697214.
• 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. PMID 14988267.
• Kublaoui BM, Holder JL, Tolson KP, Gemelli T, Zinn AR (Oct 2006). "SIM1 overexpression partially rescues agouti yellow and diet-induced obesity by normalizing food intake". Endocrinology. 147 (10): 4542–9. doi:10.1210/en.2006-0453. PMID 16709610.