Context: Whether mutations in the melanocortin-4 receptor (MC4R) are the cause of binge eating disorder was controversial. In addition, the penetrance of mutations in the MC4R in causing obesity was debated.
Objective: We investigated whether MC4R variants identified from obese patients with binge eating disorder (T11A, F51L, T112M, and M200V) and variants identified in nonobese (I102T, F202L, and N240S) or obese (I102S, A154D, and S295P) subjects cause loss-of-function and what are the defects.
Design: Variant or wild-type MC4Rs were expressed in HEK293 cells and examined for their pharmacological characteristics.
Setting: The study setting was in vitro bench-top laboratory experiments.
Main outcome measures: Ligand binding, signaling, and cell surface expression of the variant MC4Rs were compared with wild-type MC4R.
Results: Our data clearly show a loss-of-function phenotype in vitro for I102T and N240S variants identified in nonobese individuals. Furthermore, not all MC4R variants identified in obese subjects exhibit a loss-of-function phenotype in vitro. Finally, the MC4R variants T11A, F51L, T112M, and M200V identified from patients with binge eating disorder displayed normal function with regards to the parameters measured in our study.
Conclusions: Patients harboring loss-of-function MC4R mutations do not always exhibit obesity. Novel MC4R variant identified from an obese patient cannot be assumed to be the cause of obesity without demonstrating a loss-of-function phenotype in vitro for the variant MC4R. Whether MC4R mutations are involved in the pathogenesis of binge eating disorder needs additional investigation.