View source for SIM1

{{Short description|Genetic protein}}
{{Infobox gene}}
'''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]].<ref name="pmid9199934">{{cite journal | vauthors = Chrast R, Scott HS, Chen H, Kudoh J, Rossier C, Minoshima S, Wang Y, Shimizu N, Antonarakis SE | title = 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 | journal = Genome Research | volume = 7 | issue = 6 | pages = 615–24 | date = Jun 1997 | pmid = 9199934 | pmc = 310662 | doi = 10.1101/gr.7.6.615 }}</ref><ref name="pmid11448938">{{cite journal | vauthors = Michaud JL, Boucher F, Melnyk A, Gauthier F, Goshu E, Lévy E, Mitchell GA, Himms-Hagen J, Fan CM | title = Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus | journal = Human Molecular Genetics | volume = 10 | issue = 14 | pages = 1465–73 | date = Jul 2001 | pmid = 11448938 | doi = 10.1093/hmg/10.14.1465 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SIM1 single-minded homolog 1 (Drosophila)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6492}}</ref>

==Function==
The ''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 [[Drosophila embryogenesis#Anterior-posterior axis patterning in Drosophila|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.  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]].<ref name="entrez"/>

==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<ref name="pmid10587584">{{cite journal | vauthors = Holder JL, Butte NF, Zinn AR | title = Profound obesity associated with a balanced translocation that disrupts the SIM1 gene | journal = Human Molecular Genetics | volume = 9 | issue = 1 | pages = 101–8 | date = Jan 2000 | pmid = 10587584 | doi = 10.1093/hmg/9.1.101 | doi-access = free }}</ref> and has been suggested to cause a Prader-Willi-like phenotype in other cases.<ref name="pmid12161602">{{cite journal | vauthors = 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 | title = Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype | journal = Journal of Medical Genetics | volume = 39 | issue = 8 | pages = 594–6 | date = Aug 2002 | pmid = 12161602 | pmc = 1735217 | doi = 10.1136/jmg.39.8.594 }}</ref> 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.<ref name="pmid11448938" /><ref name="pmid14982752">{{cite journal | vauthors = Holder JL, Zhang L, Kublaoui BM, DiLeone RJ, Oz OK, Bair CH, Lee YH, Zinn AR | title = Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 287 | issue = 1 | pages = E105-13 | date = Jul 2004 | pmid = 14982752 | doi = 10.1152/ajpendo.00446.2003 }}</ref> Overexpression of ''SIM1'' protects against diet induced obesity and rescues the hyperphagia of agouti yellow mice,<ref name="pmid16709610">{{cite journal | vauthors = Kublaoui BM, Holder JL, Tolson KP, Gemelli T, Zinn AR | title = SIM1 overexpression partially rescues agouti yellow and diet-induced obesity by normalizing food intake | journal = Endocrinology | volume = 147 | issue = 10 | pages = 4542–9 | date = Oct 2006 | pmid = 16709610 | doi = 10.1210/en.2006-0453 | doi-access = free }}</ref> who have disrupted [[melanocortin]] signaling. The obesity and hyperphagia may be mediated by impaired melanocortin activation of [[Paraventricular nucleus|PVN]] neurons<ref name="pmid16728530">{{cite journal | vauthors = Kublaoui BM, Holder JL, Gemelli T, Zinn AR | title = Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons | journal = Molecular Endocrinology | volume = 20 | issue = 10 | pages = 2483–92 | date = Oct 2006 | pmid = 16728530 | doi = 10.1210/me.2005-0483 | doi-access = free }}</ref> and [[oxytocin]] deficiency in these mice.<ref name="pmid18451093">{{cite journal | vauthors = Kublaoui BM, Gemelli T, Tolson KP, Wang Y, Zinn AR | title = Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice | journal = Molecular Endocrinology | volume = 22 | issue = 7 | pages = 1723–34 | date = Jul 2008 | pmid = 18451093 | pmc = 2453606 | doi = 10.1210/me.2008-0067 }}</ref> It has been demonstrated that modulating SIM1 levels postnatally also leads to hyperphagia and obesity,<ref name="pmid20220015">{{cite journal | vauthors = Tolson KP, Gemelli T, Gautron L, Elmquist JK, Zinn AR, Kublaoui BM | title = Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression | journal = The Journal of Neuroscience | volume = 30 | issue = 10 | pages = 3803–12 | date = Mar 2010 | pmid = 20220015 | pmc = 3285557 | doi = 10.1523/JNEUROSCI.5444-09.2010 }}</ref><ref name="pmid16807340">{{cite journal | vauthors = Yang C, Gagnon D, Vachon P, Tremblay A, Levy E, Massie B, Michaud JL | title = Adenoviral-mediated modulation of Sim1 expression in the paraventricular nucleus affects food intake | journal = The Journal of Neuroscience | volume = 26 | issue = 26 | pages = 7116–20 | date = Jun 2006 | pmid = 16807340 | pmc =  6673926| doi = 10.1523/JNEUROSCI.0672-06.2006 | doi-access = free }}</ref> suggesting a physiological role for SIM1 separate from its role in development.

==Interactions==
SIM1 has been shown to [[Protein-protein interaction|interact]] with [[aryl hydrocarbon receptor nuclear translocator]].<ref name=pmid9020169>{{cite journal | vauthors = Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O | title = Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein | journal = The Journal of Biological Chemistry | volume = 272 | issue = 7 | pages = 4451–7 | date = Feb 1997 | pmid = 9020169 | doi = 10.1074/jbc.272.7.4451 | doi-access = free }}</ref><ref name=pmid11782478>{{cite journal | vauthors = Woods SL, Whitelaw ML | title = 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 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 12 | pages = 10236–43 | date = Mar 2002 | pmid = 11782478 | doi = 10.1074/jbc.M110752200 | doi-access = free }}</ref>

==References==
{{reflist}}

==Further reading==
{{refbegin}}
* {{cite journal | vauthors = Fan CM, Kuwana E, Bulfone A, Fletcher CF, Copeland NG, Jenkins NA, Crews S, Martinez S, Puelles L, Rubenstein JL, Tessier-Lavigne M | title = Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome | journal = Molecular and Cellular Neurosciences | volume = 7 | issue = 1 | pages = 1–16 | date = Jan 1996 | pmid = 8812055 | doi = 10.1006/mcne.1996.0001 | s2cid = 11411254 }}
* {{cite journal | vauthors = Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O | title = Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein | journal = The Journal of Biological Chemistry | volume = 272 | issue = 7 | pages = 4451–7 | date = Feb 1997 | pmid = 9020169 | doi = 10.1074/jbc.272.7.4451 | doi-access = free }}
* {{cite journal | vauthors = Holder JL, Butte NF, Zinn AR | title = Profound obesity associated with a balanced translocation that disrupts the SIM1 gene | journal = Human Molecular Genetics | volume = 9 | issue = 1 | pages = 101–8 | date = Jan 2000 | pmid = 10587584 | doi = 10.1093/hmg/9.1.101 | doi-access = free }}
* {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = Nov 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
* {{cite journal | vauthors = Woods SL, Whitelaw ML | title = 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 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 12 | pages = 10236–43 | date = Mar 2002 | pmid = 11782478 | doi = 10.1074/jbc.M110752200 | doi-access = free }}
* {{cite journal | vauthors = 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 | title = Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype | journal = Journal of Medical Genetics | volume = 39 | issue = 8 | pages = 594–6 | date = Aug 2002 | pmid = 12161602 | pmc = 1735217 | doi = 10.1136/jmg.39.8.594 }}
* {{cite journal | vauthors = Yamaki A, Kudoh J, Shimizu N, Shimizu Y | title = A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2 | journal = Biochemical and Biophysical Research Communications | volume = 313 | issue = 3 | pages = 482–8 | date = Jan 2004 | pmid = 14697214 | doi = 10.1016/j.bbrc.2003.11.168 | doi-access = free }}
* {{cite journal | vauthors = Meyre D, Lecoeur C, Delplanque J, Francke S, Vatin V, Durand E, Weill J, Dina C, Froguel P | title = A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2 | journal = Diabetes | volume = 53 | issue = 3 | pages = 803–11 | date = Mar 2004 | pmid = 14988267 | doi = 10.2337/diabetes.53.3.803 | doi-access = free }}
* {{cite journal | vauthors = Kublaoui BM, Holder JL, Tolson KP, Gemelli T, Zinn AR | title = SIM1 overexpression partially rescues agouti yellow and diet-induced obesity by normalizing food intake | journal = Endocrinology | volume = 147 | issue = 10 | pages = 4542–9 | date = Oct 2006 | pmid = 16709610 | doi = 10.1210/en.2006-0453 | doi-access = free }}
{{refend}}

{{Transcription factors|g1}}

[[Category:PAS-domain-containing proteins]]