Identification and functional characterization of a missense mutation in resistin in two patients with severe obesity and insulin resistance

Abstract

Objective: In this study, we hypothesized that mutations in the resistin encoding gene, RETN, may cause a monogenic form of obesity. Design/methods: We screened the coding region of RETN in 81 morbidly obese adults, 263 overweight and obese children/adolescents, and 116 healthy lean subjects. In vitro experiments include qPCR, ELISA, and western blot for WT and mutant resistin transfected into 3T3-L1 adipocytes. Results: Mutation analysis identified five sequence variants in our patient populations:0 -UTR C100 A/G, T73T, IV3-61 C/A, and C78S. In our control population, we only found the 3 0 -UTR C87 G/A variant. We started functional experiments for the C78S mutation that was found in a 20-year-old obese male (body mass index (BMI)Z39.7 kg/m 2 ) and his obese mother (BMIZ31.9 kg/m 2 ). In vitro testing demonstrated that the mutation does not impair mRNA expression. We identified a 100-fold lower extracellular protein concentration for mutant resistin compared with WT levels using a resistin ELISA on cell culture medium (PZ4.87!10 K6 ). We also detected a decreased intracellular concentration for the mutant protein (tenfold lower relative levels, PZ0.007). The plasma resistin levels of the proband and his mother, however, did not differ significantly from lean control individuals. Conclusions: In conclusion, we identified the first missense mutation in resistin in a morbidly obese proband and his obese mother. Functional testing of the mutant protein suggests that the C78S mutant protein is degraded, possibly resulting in a decreased extracellular concentration, which may predispose to obesity. 164 927-936 European Journal of Endocrinology

De novo 19p13.2 microdeletion encompassing the insulin receptor and resistin genes in a patient with obesity and learning disability

“…A recent publication described a heterozygous C78S missense mutation in RETN in an obese patient [Beckers et al, ]. The mutation was inherited from one of the two obese parents.…”

In Silico Analysis of Coding/Noncoding SNPs of Human RETN Gene and Characterization of Their Impact on Resistin Stability and Structure

“…Beckers et al identified the first missense mutation C78S in resistin in a morbidly obese proband and his obese mother. This finding encourages the study of variants in the RETN gene coding region to elucidate their involvement in pathogenesis [18]. It was estimated that genetic factors can explain up to 70% of the variation in circulating resistin levels [19].…”