RESUMO
CONTEXT: Mutations in the MC4R gene are the most common cause of monogenic obesity, and there are few studies on mutations in the promoter region. OBJECTIVE: The objective of the study was to sequence the promoter region of the MC4R gene in a cohort of obese children to identify rare variants. DESIGN, SETTING, AND PATIENTS: A region 1500 bp upstream of the MC4R gene was sequenced in 267 unrelated local children younger than 10 years, with body weight of at least 150% of ideal. An 891-bp upstream region of the MC4R gene was cloned into a luciferase reporter vector for reporter gene assays. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: The basal transcriptional activity of the MC4R promoter was analyzed in human embryonic kidney 293 cells using reporter gene assays. RESULTS: Three rare variants were detected: c.-803A>G, c.-105C>G, and c.-216C>T. The novel c.-803A>G variant was found in a 9-year-old severely obese Malay boy. This variant was not found in his severely obese mother but was present in his overweight father, who had type 2 diabetes, and also in his normal-weight brother. The novel c.-105C>G variant was found in an obese 9-year-old Malay boy. The c.-216C>T variant was found in an obese Chinese girl with Down's syndrome. The transcriptional activities of the c.-803A>G and c.-105C>G promoters were significantly reduced compared with the wild type but not the c.-216C>T promoter. CONCLUSIONS: We have described, for the first time, two novel human MC4R gene promoter variants found in obese children that resulted in a decrease in basal transcriptional activity.