eP012: Biochemical characterization of single minded-1 missense variants associated with severe obesity


      Single Minded-1 (SIM1) is a transcription factor involved in development and function of the hypothalamic paraventricular nucleus, a site critical for the body weight–regulating function of the melanocortin-4 receptor (MC4R) pathway. Consistent with its MC4R pathway involvement, rare loss-of-function (LOF) variants in SIM1 are associated with severe early-onset obesity and hyperphagia, hallmark features of rare genetic diseases of obesity. To better understand the contribution of SIM1 variants to severe clinical obesity, we performed functional biochemical characterization of rare SIM1 variants in Rhythm’s database of approximately 40,000 individuals with severe obesity.


      Functional impact of SIM1 missense variants was assessed using a well-established and controlled hypoxia response element- (HRE-) luciferase reporter gene assay.


      In total, 213 missense SIM1 variants were identified in individuals with severe obesity; 93 have not been previously described, while 197 have not been functionally assessed. Biochemical characterization of all 213 SIM1 variants was performed to determine impact on protein function. Of the 213 variants, 3 exhibited complete LOF, 93 exhibited moderate LOF, and 117 exhibited WT-like activity. Thus, nearly half of the rare SIM1 missense variants, including 40 novel variants, observed in obese individuals exhibit LOF in a biochemical assay.


      These findings provide important insights into the SIM1 variant landscape and may help in the future diagnosis and treatment of individuals with SIM1 deficiency obesity.