Functional Studies on Twenty Novel Naturally Occurring Melanocortin-4 Receptor Mutations

Zhi-Qiang Wang (1, 2) , Ya-Xiong Tao (2)

1 Yangzhou University
2 Department of Anatomy

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor critically involved in regulating energy balance. MC4R activation results in decreased food intake and increased energy expenditure. Genetic and pharmacological studies demonstrated that the MC4R regulation of energy balance is conserved from fish to mammals. In humans, more than 150 naturally occurring mutations in the gene have been identified. Functional study of mutant MC4Rs is an important component in proving the causal link between mutation and obesity as well as the basis of personalized medicine. In this article, we studied 20 mutations that were either not characterized or not fully characterized. We showed that 11 mutants had decreased or absent cell surface expression. D126Y was defective in ligand binding. Three mutants were constitutively active but had decreased cell surface expression. Eleven mutants had decreased basal signaling, with two mutants defective only in this parameter, suggesting that impaired basal signaling might also be a cause of obesity. Five mutants had normal functions. In summary, we provided detailed functional data for further studies on identifying therapeutic approaches for personalized medicine to treat patients harboring these mutations.

Mots clés: AgRP; GPCR; MC3R; MC4R; MSH; WT; Melanocortin-4 receptor; naturally occurring mutation; intracellular retention; binding; signaling

Domaines: Biochimie, Biologie Moléculaire

Zhi-Qiang Wang, Ya-Xiong Tao. Functional Studies on Twenty Novel Naturally Occurring Melanocortin-4 Receptor Mutations. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2011, 1812 (9), pp.1190. ⟨10.1016/j.bbadis.2011.06.008⟩. ⟨hal-00719827⟩