Correspondence

Binge Eating as a Phenotype of Melanocortin 4 Receptor Gene Mutations

N Engl J Med 2003; 349:606-609August 7, 2003

Article

To the Editor:

Branson et al. (March 20 issue)1 found DNA sequence changes in the melanocortin 4 receptor (MC4R) gene in 24 of 469 severely obese subjects and confirmed binge eating in all the carriers examined. Of the 25 sequence changes identified, 11 (44 percent) were the Val103Ile change that my colleagues and I reported originally as a sequence variant that was not associated with obesity or obesity-related phenotypes.2 The notion that the Val103Ile change represents a variant of little physiologic significance has been supported by many functional and genetic studies.3 The only exception is a study that showed marginal evidence of an association between the Val103Ile change and lean phenotypes.4 Therefore, there is insufficient evidence to validate the inclusion of the Val103Ile change as an obesity-related MC4R mutation. The data presented by Branson et al., including the absence of a correlation between body fat and serum leptin levels in carriers of changes in MC4R, should be interpreted carefully. I would also point out that the Ser343Ser variant in the leptin receptor gene, which Branson et al. describe as a novel mutation, has been reported previously as a mere nonfunctional variant.5

Takanari Gotoda, M.D.
Tokyo Women's Medical University, Tokyo 162-8666, Japan
gotoda@dmc.twmu.ac.jp

5 References

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   Branson R, Potoczna N, Kral JG, Lentes K-U, Hoehe MR, Horber FF. Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med 2003;348:1096-1103
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To the Editor:

MC4R mutations have previously been reported in binge-eating disorder and bulimia.1,2 As part of an ongoing trial,3 we compared four groups of persons matched for age and sex: normal-weight control subjects, obese control subjects who did not intend to lose weight, obese subjects seeking conventional treatment, and obese subjects seeking surgery. The MC4R was screened by denaturing high-performance liquid chromatography; aberrant polymerase-chain-reaction products were sequenced.1 Diagnosis of lifetime binge-eating disorder was ascertained by means of a standardized interview for eating disorders.3 We were not able to confirm the association of MC4R mutations with binge-eating disorder (Table 1Table 1Binge-Eating Disorder and Mutations in the Melanocortin 4 Receptor Gene (MC4R) in Normal-Weight and Obese Subjects.). Only a single obese subject heterozygous for a functionally relevant MC4R mutation (Gly181Asp) was detected among the 436 obese subjects, 311 of whom had a body-mass index greater than 40. Two polymorphisms (Val103Ile and Ile251Leu) have previously been shown to occur with similar frequencies in both obese subjects and controls and have functional properties indistinguishable from those of the wild-type receptor1,2,4; their inclusion in the study by Branson et al. was thus not warranted.

Stephan Herpertz, M.D.
Winfried Siffert, M.D.
University of Essen, 45147 Essen, Germany
stephan.herpertz@uni-essen.de

Johannes Hebebrand, M.D.
University of Marburg, 35039 Marburg, Germany

4 References

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To the Editor:

In the study reported by Branson et al., 18 of the 24 obese subjects with MC4R variants harbored variants that signal normally in vitro and that are prevalent in nonobese subjects (Table 1Table 1Frequency of Common Variants in the Melanocortin 4 Receptor.).

Mutations in MC4R are an important and highly penetrant cause of severe early-onset obesity.3 We are concerned that use of the term “mutation,” when applied to the type of sequence variant described by Branson et al., may cause confusion among clinicians and lead to inappropriate clinical decisions. We suggest that an MC4R mutation be viewed as causative only if it cosegregates with obesity in pedigrees, is absent in ethnically matched controls, and impairs the function of the encoded receptor. Given the uncertainties regarding the pathogenic nature of the variants described by Branson et al., we conclude that although the relation between MC4R function and the human appetite has been convincingly described and quantitated1 the putative link between MC4R variants and binge eating requires further scrutiny.

Ismaa S. Farooqi, M.D., Ph.D.
Giles S. Yeo, Ph.D.
Stephen O'Rahilly, M.D.
University of Cambridge, Cambridge CB2 2QQ, United Kingdom
ifarooqi@hgmp.mrc.ac.uk

3 References

1. 1

   Gotoda T, Scott J, Aitman TJ. Molecular screening of the human melanocortin-4 receptor gene: identification of a missense variant showing no association with obesity, plasma glucose, or insulin. Diabetologia 1997;40:976-979
   CrossRef | Web of Science | Medline

2. 2

   Farooqi IS, Keogh JM, Yeo GSH, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003;348:1085-1095
   Full Text | Web of Science | Medline

3. 3

   Marti A, Corbalan MS, Forga L, et al. A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population. Int J Obes Relat Metab Disord 2003;27:385-388
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Author/Editor Response

Responding to our study of clinically defined binge-eating disorder, Gotoda, Herpertz et al., and Farooqi et al. criticize our inclusion of patients with MC4R variants, or “mutations” as we call them, in keeping with the Human Genome Project (http://www.ornl.gov/techresources/human_genome/home.html) definition.1 We caution against ruling out the possibility that the variants they classify as having little physiologic or functional significance may indeed, in clinical, real-life testing, prove to be pathogenic.2 This was the case with the Ser343Ser polymorphism3 (which we mistakenly described as novel). We question the validity of a “diagnosis of lifetime binge-eating disorder” on the basis of patients' memory decades later, especially in conjunction with the inferior sensitivity of denaturing high-performance liquid chromatography to detect polymorphisms. We believe that the discordance in the reported findings points to the real possibility of differences in the selection of probands, a well-recognized concern in studies of obesity.4,5 Our correlations (or the absence thereof) between body fat and serum leptin levels, after adjustment for the presence of binge-eating disorder and after matching for range of body fat, are valid (bingeing noncarriers, r=0.53 and P=0.03; nonbingeing noncarriers, r=0.46, P<0.001), but they do not suggest a mechanism for a putative communication between the central melanocortin system and body fat.

Our population of patients with MC4R abnormalities all had a clinically well-defined binge-eating disorder. Furthermore, in support of the phenotypic importance of the polymorphisms we reported, 19 of the carriers of MC4R variants lost significantly less weight and had less improvement in components of the metabolic syndrome during three years of follow-up while on a low-calorie diet after laparoscopic banding than 155 matched noncarriers (Table 1Table 1Weight Loss and the Metabolic Syndrome in 19 Carriers and 155 Noncarriers of Mutations in the Melanocortin 4 Receptor (MC4R) Gene.). They also had more gastric complications associated with banding (mean [±SEM] number of complications per patient, 1.17±0.27 vs. 0.36±0.04; P<0.001), including increased esophageal diameter on esophagography (8.3±1.1 mm vs. 3.7±0.3 mm, P=0.003).

Obviously, the polymorphisms and variants, whether active in vitro or not, have powerful clinical relevance, and identifying them may well be appropriate to guide clinical decisions in this era of genomic medicine.

John G. Kral, M.D., Ph.D.
State University of New York Downstate Medical Center, Brooklyn, NY 11203

Klaus-Ulrich Lentes, Ph.D.
Bioscientia, D-55218 Ingelheim, Germany

Fritz Horber, M.D.
Klinik Hirslanden, CH-8008 Zurich, Switzerland
genetics@obex.ch

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    E H Young, N J Wareham, S Farooqi, A Hinney, J Hebebrand, A Scherag, S O'Rahilly, I Barroso, M S Sandhu. (2007) The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals. International Journal of Obesity 31:9, 1437-1441
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    M. C. Ochoa, C. Azcona, H. Biebermann, H. Brumm, C. Razquin, A.-K. Wermter, J. A. Martínez, J. Hebebrand, A. Hinney, M. J. Moreno-Aliaga, A. Marti, . (2007) A novel mutation Thr162Arg of the melanocortin 4 receptor gene in a Spanish children and adolescent population. Clinical Endocrinology 66:5, 652-658
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    Tiffany M. Stewart. (2006) Genes and Binge Eating: Are We Missing the Target?. Obesity Management 2:6, 223-226
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    Mark D DeBoer, Daniel L Marks. (2006) Therapy insight: use of melanocortin antagonists in the treatment of cachexia in chronic disease. Nature Clinical Practice Endocrinology &#38; Metabolism 2:8, 459-466
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    Mark D. DeBoer, Daniel L. Marks. (2006) Cachexia: lessons from melanocortin antagonism. Trends in Endocrinology & Metabolism 17:5, 199-204
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    Karine Clément. (2005) Genetics of human obesity. Proceedings of the Nutrition Society 64:02, 133-142
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    George A. Bray, Catherine M. Champagne. (2005) Beyond Energy Balance: There Is More to Obesity than Kilocalories. Journal of the American Dietetic Association 105:5, 17-23
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    Randy J. Seeley, Deborah L. Drazen, Deborah J. Clegg. (2004) THE CRITICAL ROLE OF THE MELANOCORTIN SYSTEM IN THE CONTROL OF ENERGY BALANCE. Annual Review of Nutrition 24:1, 133-149
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