The Human MC4R Promoter
Characterization and Role in Obesity
- Cecile Lubrano-Berthelier1,
- Martha Cavazos1,
- Catherine Le Stunff2,
- Kurt Haas1,
- Astrid Shapiro1,
- Sumei Zhang1,
- Pierre Bougneres2 and
- Christian Vaisse1
- 1Department of Medicine, Division of Endocrinology and the Diabetes Center, University of California San Francisco, San Francisco, California
- 2Department of Pediatric Endocrinology, Saint Vincent de Paul Hospital, University Rene Descartes, Paris, France
- Address correspondence and reprint requests to Dr. Christian Vaisse, Diabetes Center, University of California San Francisco, 513 Parnassus Ave., Box 0573, San Francisco, CA 94143-0573. E-mail: vaisse{at}medicine.ucsf.edu
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.
- 5′RACE, 5′
- rapid amplification of cDNA ends
- GPCR, G-protein–coupled receptor
- MC4R, melanocortin 4 receptor
- SNP, single nucleotide polymorphism
- UCSF, University of California San Francisco
- UTR, untranslated region
Footnotes
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- Accepted August 21, 2003.
- Received July 16, 2003.
- DIABETES
