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Diabetes 52:2996-3000, 2003
© 2003 by the American Diabetes Association, Inc.
Brief Genetics Report |
The Human MC4R Promoter
Characterization and Role in Obesity
1 Department of Medicine, Division of Endocrinology and the Diabetes Center, University of California San Francisco, San Francisco, California
2 Department of Pediatric Endocrinology, Saint Vincent de Paul Hospital, University Rene Descartes, Paris, France
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.
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
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