Identification and characterization of two novel melanocortin-3 receptor mutations in Chinese obese individuals

Abstract The melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R), known as neural melanocortin receptors, have been implicated to be critical components of the hypothalamic leptin-melanocortin pathway and related to obesity pathogenesis. In contrast to extensive evidence from physiologic, biological, genetic studies demonstrating that MC4R is a critical regulator in obesity, whether MC3R mutation causes obesity is still controversial. In the present study, we screened for coding variants in the MC3R gene of 176 obese individuals (mean BMI 34.84 ± 0.19 kg/m2) and 170 lean controls (mean BMI 20.70 ± 0.08 kg/m2) to assess the prevalence of MC3R mutations in a Chinese cohort. Two novel mutations, A33D (c.C98 > A) and A259T (c.G775 > A), were identified in two subjects with morbid obesity, respectively. A259T was also identified in the carrier's sibling. In vitro functional studies showed that A33D was defective in the cAMP signaling pathway, whereas A259T MC3R had defective maximal binding and cAMP generation in response to NDP- and α-MSH, likely due to decreased cell surface expression. In addition, we showed that A33D and A259T were biased receptors and defect in constitutive activation of ERK1/2 signaling through MC3R might be a cause for morbid obesity. Our sequencing and co-segregation studies combined with comprehensive functional analysis demonstrated that A259T might be predisposing to obesity. Further investigations in larger cohorts will be needed in order to define this association and the specific phenotypic characteristics resulting from these mutations.