title: Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative effect caused by receptor dimerization.
abstract: Mutations in the melanocortin-4 receptor (MC4R) gene are the most frequent monogenic causes of severe obesity. Most mutations have been described as heterozygous with loss of function, suggesting that haploinsufficiency is the most likely mechanism of dominant inheritance. We detected a heterozygous mutation, D90N, in a patient with severe early-onset obesity. Functional characterization of the mutant receptor revealed normal cell-surface expression and binding properties but loss of signal transduction activity. In coexpression studies of wild-type (WT)-MC4R and D90N, the mutant receptor had a dominant-negative effect on WT-receptor function. Further investigation of this effect with sandwich enzyme-linked immunosorbent assays and fluorescence resonance energy transfer studies showed that the WT-MC4R and the D90N mutant form homodimers and heterodimers. We hypothesize that the dominant-negative effect of the D90N mutation is caused by a functionally altered WT-MC4R/D90N receptor heterodimer. These findings necessitate the reinvestigation of other heterozygous MC4R missense mutations to discriminate between haploinsufficiency and a dominant-negative effect. The finding of receptor dimerization highlights a more complex hypothalamic signaling network governing the regulation of body weight.
authors.affiliation: Otto Heubner Centrum für Kinderheilkunde und Jugendmedizin, Pädiatrische Endokrinologie, Charité Campus Virchow-Klinikum, Humboldt-Universität zu Berlin, Berlin, Germany. heike.biebermann@charite.de
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Andrea
authors.initials: A
authors.lastname: Elsner
authors.forename: Vladimir
authors.initials: V
authors.lastname: Chubanov
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
mesh_terms: D017668:Age of Onset; D000818:Animals; D019556:COS Cells; D016022:Case-Control Studies; D015331:Cohort Studies; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D005787:Gene Frequency; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D007223:Infant; D009154:Mutation; D009765:Obesity / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D014162:Transfection
chemical_list: C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4