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- Title
Genetic find Functional Analyses of Melanocortin-4 Receptor Variants in Chinese Subjects.
- Authors
Fang, Qichen; Jia, Weiping; Zhang, Rong; Wang, Congrong; Hu, Cheng; Shao, Xinyu; Xiang, Kunsan
- Abstract
In the previous study, we had identified four variants in the melanocortin-4 receptor (MC4R) gene in Chinese subjects. Three polymorphisms (nt-216C/T, nt-178A/C and V103I) were detected in both obese and non-obese subjects and one missense mutation (F261S) was found in an early-onset obesity pedigree. The aim of this study is to investigate the association between the polymorphisms of MC4R gene and obesity, and to analyze the functional defect of F261S mutation in MC4R. The genotypes of the three polymorphisms were determined through DNA sequencing in 563 Chinese from Shanghai, including 258 individuals with body mass index (BMI) over 30kg/m² and 305 individuals with BMI less than 23kg/m². |D'| and r² value were calculated. Signaling and cell surface expression of F261S MC4R were compared with that of wild-type MC4R in mammalian cells. Our data showed: 1. The frequencies of nt216C/T, nt-178A/C and Val103Ile were 1.6%, 2.5% and 3.2% respectively. Three polymorphisms were in low linkage disequilibrium. Logistic regression showed that the Val103Ile variant was an independent risk factor for obesity (OR=0.414, P=0.040). The frequency of Ile was less in the obese individuals compared with the controls. 2. α-MSH activation of MC4R was impaired by the F261S mutation. The α-MSH-stimulated reporter gene activity was significantly reduced in cells expressing F261S MC4R, with a maximal response equal to 57% of wild-type MC4R and the F261S mutation also led to a great change in the EC[sub 50] value compared with the wild-type receptor (P<0.01). By immunofluorescent assay, a marked reduction in the plasma membrane localization of the MC4R was detected in cells expressing the F261S mutant receptor. In conclusion: Val103Ile variant of MC4R gene was associated with obesity in Chinese. The decreased response to α-MSH resulted from the intracellular retention maybe the major cause of early-onset obesity of the F261S pedigree.
- Subjects
GENETIC polymorphisms; OVERWEIGHT persons; OBESITY; GENETIC mutation; NUCLEOTIDE sequence; BODY mass index
- Publication
Diabetes, 2007, Vol 56, pA465
- ISSN
0012-1797
- Publication type
Article