SIM1 and obesity due to melanocortin 4 receptor deficiency: One human SIM1 early onset obesity variant, SIM1.R171H [80], is within the PAS-A -AT-Hook region predicted to contact DNA (Supplementary Fig. S7A) and has been shown to possess only 30% of wildtype (WT) SIM1 activity, a trait that is shared with its paralog SIM2 [58, 80].