In a 13-year-old obese girl and her father, Lee et al. (2002) identified a heterozygous mutation (I183N; 155540.0001) in the MC3R gene. Functional characterization of the I183N mutant by Tao and Segaloff (2004) demonstrated a complete lack of ... In a 13-year-old obese girl and her father, Lee et al. (2002) identified a heterozygous mutation (I183N; 155540.0001) in the MC3R gene. Functional characterization of the I183N mutant by Tao and Segaloff (2004) demonstrated a complete lack of signaling in response to agonist stimulation. Feng et al. (2005) analyzed the MCR3 gene in 190 overweight and 160 nonoverweight children and found that 29 (8.2%) children were double homozygous for 2 missense variants, T6L and V81I. The double homozygous children were significantly heavier (p less than 0.0001), had more body fat (p less than 0.001), and had greater plasma leptin (p less than 0.0001) and insulin concentrations (p less than 0.001) and greater insulin resistance (p less than 0.008) than wildtype or heterozygous children. Both sequence variants were more common in African American than in Caucasian children. Mencarelli et al. (2008) sequenced the MC3R gene in 290 obese individuals and 215 normal-weight controls and identified 3 heterozygous mutations present in 3 obese individuals, respectively, that were not present in controls. Although there were only a limited number of family members available for study, there appeared to be cosegregation of the mutations with the obese phenotype. In vitro functional studies of 1 of the mutations (I335S; 155540.0002) showed intracellular retention and complete loss of function of the mutant receptor. Calton et al. (2009) studied MC3R variants detected in a total of 1,821 North American adults (889 severely obese and 932 lean controls) from 2 cohorts, and did not find an association between variants in the MC3R gene and severe obesity in this population. Mencarelli et al. (2011) evaluated the entire coding region of MC3R in 839 severely obese individuals and 967 lean controls of French or Italian origin and performed in vitro functional analysis of the detected mutations. The total prevalence of rare MC3R variants was not significantly different in obese individuals compared to controls (p = 0.18). However, the prevalence of mutations associated with reduced MC3R signaling was significantly higher in the obese group (p = 0.22), suggesting that impairment of MC3R signaling is associated with obesity.