Functional analyses of melanocortin-4 receptor mutations identified from patients with binge eating disorder and nonobese or obese subjects.
نویسندگان
چکیده
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.
منابع مشابه
Identification and functional characterization of three novel human melanocortin-4 receptor gene variants in an obese Chinese population.
OBJECTIVE Mutations in the melanocortin-4 receptor gene (MC4R) are the most common monogenic form of human obesity. However, the contribution of MC4R mutations to obesity in Chinese has not been investigated. We studied the frequency of MC4R mutations in an obese southern Chinese population and the functional consequences of the novel variants identified. METHODS We screened for MC4R mutation...
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ورودعنوان ژورنال:
- The Journal of clinical endocrinology and metabolism
دوره 90 10 شماره
صفحات -
تاریخ انتشار 2005