title: Functional analyses of melanocortin-4 receptor mutations identified from patients with binge eating disorder and nonobese or obese subjects.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Variant or wild-type MC4Rs were expressed in HEK293 cells and examined for their pharmacological characteristics.
  
  
  METHODS
  The study setting was in vitro bench-top laboratory experiments.
  
  
  METHODS
  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.
authors: Department of Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City 52242, USA. taoyaxi@vetmed.auburn.edu
authors: Ya-Xiong
authors: YX
authors: Tao
authors: Deborah L
authors: DL
authors: Segaloff
mesh_terms: D002032:Bulimia / Q000235:genetics*; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D004247:DNA / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D018613:Microscopy, Confocal; D016296:Mutagenesis; D009154:Mutation / Q000502:physiology; D009765:Obesity / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D044105:Receptor, Melanocortin, Type 4; D011956:Receptors, Cell Surface; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D004247:DNA; D000242:Cyclic AMP