title: The human MC4R promoter: characterization and role in obesity.
abstract: Heterozygous mutations in the coding sequence of the serpentine melanocortin 4 receptor (MC4R) are the most frequent genetic cause of severe human obesity. Since haploinsufficiency has been proposed as a causal mechanism of obesity associated with these mutations, reduction in gene transcription caused by mutations in the transcriptionally essential regions of the MC4R promoter may also be a cause of severe obesity in humans. To test this hypothesis we defined the minimal promoter region of the human MC4R and evaluated the extent of genetic variation in this region compared with the coding region in two cohorts of severely obese subjects. 5'RACE followed by functional promoter analysis in multiple cell lines indicates that an 80-bp region is essential for the transcriptional activity of the MC4R promoter. Systematic screening of 431 obese children and adults for mutations in the coding sequence and the minimal core promoter of MC4R reveals that genetic variation in the transcriptionally essential region of the MC4R promoter is not a significant cause of severe obesity in humans.
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California 94143-0573, USA.
authors.forename: Cecile
authors.initials: C
authors.lastname: Lubrano-Berthelier
authors.forename: Martha
authors.initials: M
authors.lastname: Cavazos
authors.forename: Catherine
authors.initials: C
authors.lastname: Le Stunff
authors.forename: Kurt
authors.initials: K
authors.lastname: Haas
authors.forename: Astrid
authors.initials: A
authors.lastname: Shapiro
authors.forename: Sumei
authors.initials: S
authors.lastname: Zhang
authors.forename: Pierre
authors.initials: P
authors.lastname: Bougneres
authors.forename: Christian
authors.initials: C
authors.lastname: Vaisse
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D002648:Child; D015331:Cohort Studies; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
chemical_list: C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4