SIM1

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 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.

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 haploinsufficiency 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.

References

References

1. (Jun 1997). "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 Research.
2. (Jul 2001). "Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus". Human Molecular Genetics.
3. "Entrez Gene: SIM1 single-minded homolog 1 (Drosophila)".
4. (Jan 2000). "Profound obesity associated with a balanced translocation that disrupts the SIM1 gene". Human Molecular Genetics.
5. (Aug 2002). "Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype". Journal of Medical Genetics.
6. (Jul 2004). "Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice". American Journal of Physiology. Endocrinology and Metabolism.
7. (Oct 2006). "SIM1 overexpression partially rescues agouti yellow and diet-induced obesity by normalizing food intake". Endocrinology.
8. (Oct 2006). "Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons". Molecular Endocrinology.
9. (Jul 2008). "Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice". Molecular Endocrinology.
10. (Mar 2010). "Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression". The Journal of Neuroscience.
11. (Jun 2006). "Adenoviral-mediated modulation of Sim1 expression in the paraventricular nucleus affects food intake". The Journal of Neuroscience.
12. (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.
13. (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.