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Melanocortin 4 Receptor Sequence Variations Are Seldom a Cause of Human Obesity: The Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis Cohort

Human Genomics Laboratory (P.J., O.U., T.R., E.E.S., C.B.), Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808; Department of Internal Medicine and Biocenter Oulu (O.U.), University of Oulu, FIN-90220 Oulu, Finland; School of Kinesiology and Leisure Studies (A.S.L.), University of Minnesota, Minneapolis, Minnesota 55455; Division of Biostatistics and Departments of Genetics and Psychiatry (D.C.R.), Washington University School of Medicine, St. Louis, Missouri 63110; Department of Kinesiology (J.S.S.), Indiana University, Bloomington, Indiana 46405; Department of Health and Kinesiology (J.H.W.), Texas A&M University, College Station, Texas 77843-4243; Departments of Medicine (L.L., L.S.) and Diagnostic Radiology (L.L.), Sahlgrenska University Hospital, 413 45 Göteborg, Sweden; and Department of Surgery (G.S.C.), College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38112

Address all correspondence and requests for reprints to: Claude Bouchard, Ph.D., Human Genomics Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808-4124. E-mail: bouchac{at}pbrc.edu.

Abstract

The prevalence of mutations within and in the flanking regions of the gene encoding the melanocortin 4 receptor was investigated in severely obese and normal-weight subjects from the Swedish Obese Subjects study, the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family study, and a Memphis cohort. A total of 433 white and 95 black subjects (94% females) were screened for mutations by direct sequencing. Three previously described missense variants and nine novel (three missense, six silent) variants were detected. None of them showed significant association with obesity or related phenotypes. In addition, two novel deletions were found in two heterozygous obese women: a -65_-64delTG mutation within the 5' noncoding region and a 171delC frameshift mutation predicted to result in a truncated nonfunctional receptor. No pathogenic mutations were found among obese blacks or nonobese controls. Furthermore, none of the null mutations found in other populations was present in this sample. In conclusion, our results do not support the prevailing notion that sequence variation in the melanocortin 4 receptor gene is a frequent cause of human obesity.

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