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  • Original Article
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Screening for melanocortin-4 receptor mutations in a cohort of Belgian morbidly obese adults and children

International Journal of Obesity volume 30, pages 221–225 (2006)Cite this article

Abstract

Objective:

To investigate whether pathogenic melanocortin-4 receptor (MC4R) mutations are a common cause of obesity in Belgium.

Design:

Cross-sectional mutation analysis.

Subjects:

In total, 95 morbidly obese adults (mean age 44.02±11.35 years; mean BMI 47.87±4.17 kg/m2) and 123 obese children and adolescents were screened for mutations in MC4R (mean age 16.56±2.58 years; BMI>95th percentile for age and sex; mean % overweight 170.86±23.63).

Measurements:

A series of anthropometric (e.g. weight, height, waist, hip), biochemical and clinical measurements were performed on all subjects. The entire coding region of MC4R was screened using DHPLC, a highly sensitive and specific method for mutation analysis. Direct sequencing was performed when the chromatogram deviated from the WT pattern.

Results:

Mutation screening of a cohort of Belgian obese adults and children did not detect any pathogenic mutations as only the previously described polymorphisms Val103Ile, Thr112Met and Ile251Leu were detected.

Conclusion:

Pathogenic mutations in MC4R are not a common cause of obesity in a Belgian population of obese adults, children and adolescents.

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References

  1. Snyder EE, Walts B, Pérusse L, Chagnon YC, Weisnagel SJ, Rankinen T et al. The human obesity gene map: the 2003 update. Obes Res 2004; 12: 369–439.

    Article  CAS  Google Scholar 

  2. Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson SJ et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem 1993; 268: 15174–15179.

    CAS  PubMed  Google Scholar 

  3. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997; 278: 135–138.

    Article  CAS  Google Scholar 

  4. Cone RD . The central melanocortin system and energy homeostasis. Trends Endocrinol Metab 1999; 10: 211–216.

    Article  CAS  Google Scholar 

  5. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD . Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385: 165–168.

    Article  CAS  Google Scholar 

  6. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131–141.

    Article  CAS  Google Scholar 

  7. Vaisse C, Clement K, Guy-Grand B, Froguel P . A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nature Genet 1998; 20: 113–114.

    Article  CAS  Google Scholar 

  8. Yeo GSH, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S . A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nature Genet 1998; 20: 111–112.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. Ohshiro Y, Sanke T, Ueda K, Shimajiri Y, Nakagawa T, Tsunoda K et al. Molecular scanning for mutations in the melanocortin-4 receptor gene in obese/diabetic Japanese. Ann Hum Genet 1999; 63: 483–487.

    Article  CAS  Google Scholar 

  11. Rosmond R, Chagnon M, Bouchard C, Björntorp P . A missense mutation in the human melanocortin-4 receptor gene in relation to abdominal obesity and salivary cortisol. Diabetologia 2001; 44: 1335–1338.

    Article  CAS  Google Scholar 

  12. Dubern B, Clement K, Pelloux V, Froguel P, Girardet JP, Guy-Grand B et al. Mutational analysis of melanocortin-4 receptor, agouti-related protein, and α-melanocyte-stimulating hormone genes in severely obese children. J Pediatr 2001; 139: 204–209.

    Article  CAS  Google Scholar 

  13. Larsen LH, Echwald SM, Sorensen TI, Andersen T, Wulff BS, Pedersen O . Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity. J Clin Endocrinol Metab 2005; 90: 219–224.

    Article  CAS  Google Scholar 

  14. Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P . Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000; 106: 253–262.

    Article  CAS  Google Scholar 

  15. Hinney A, Hohmann S, Geller F, Vogl C, Hess C, Wermter AK et al. Melanocortin-4 receptor gene: case–control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. J Clin Endocrinol Metab 2003; 88: 4258–4267.

    Article  CAS  Google Scholar 

  16. O'Donovan MC, Oefner PJ, Roberts SC, Austin J, Hoogendoorn B, Guy C et al. Blind analysis of denaturing high-performance liquid chromatography as a tool for mutation detection. Genomics 1998; 52: 44–49.

    Article  CAS  Google Scholar 

  17. Wu G, Wu W, Hegde M, Fawkner M, Chong B, Love D et al. Detection of sequence variations in the adenomatous polymosis coli (APC) gene using denaturing high-performance liquid chromatography. Genetic Testing 2001; 5: 281–290.

    Article  CAS  Google Scholar 

  18. Gu W, Tu Z, Kleyn PW, Kissebah A, Duprat L, Lee J et al. Identification and functional analysis of novel human melanocortin-4 receptor variants. Diabetes 1999; 48: 635–639.

    Article  CAS  Google Scholar 

  19. Hinney A, Schmidt A, Nottebom K, Heibült O, Becker I, Ziegler A et al. Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab 1999; 84: 1483–1486.

    Article  CAS  Google Scholar 

  20. Yeo GSH, Lank EJ, Farooqi S, Keogh J, Challis BG, O'Rahilly S . Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet 2003; 12: 561–574.

    Article  CAS  Google Scholar 

  21. Farooqi IS, Yeo GSH, Keogh JM, Aminian S, Jebb SA, Butler G et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 2000; 106: 271–279.

    Article  CAS  Google Scholar 

  22. 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.

    Article  CAS  Google Scholar 

  23. Mergen M, Mergen H, Ozata M, Oner R, Oner C . A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity. J Clin Endocrinol Metab 2001; 86: 3448–3451.

    Article  CAS  Google Scholar 

  24. Ma L, Tataranni PA, Bogardus C, Baier LJ . Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians. Diabetes 2004; 53: 2696–2699.

    Article  CAS  Google Scholar 

  25. Lubrano-Berthelier C, Cavazos M, Le Stunff C, Haas K, Shapiro A, Zhang S et al. The human MC4R promoter: characterization and role in obesity. Diabetes 2003; 52: 2996–3000.

    Article  CAS  Google Scholar 

  26. Santini F, Maffei M, Ceccarini G, Pelosini C, Scartabelli G, Rosellini V et al. Genetic screening for melanocortin-4 receptor mutations in a cohort of Italian obese patients: description and functional characterization of a novel mutation. J Clin Endocrinol Metab 2004; 89: 904–908.

    Article  CAS  Google Scholar 

  27. Lubrano-Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, Weill J et al. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 2003; 12: 145–153.

    Article  CAS  Google Scholar 

  28. Branson R, Potoczna N, Kral JG, Lentes KU, Hoehe MR, Horber FF . Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med 2003; 348: 1096–1103.

    Article  CAS  Google Scholar 

  29. Jacobson P, Ukkola O, Rankinen T, Snyder EE, Leon AS, Rao DC et al. Melanocortin 4 receptor sequence variation are seldom a cause of human obesity: the Swedish obese subjects, the HERITAGE family study, and Memphis cohort. J Clin Endocrinol Metab 2002; 87: 4442–4446.

    Article  CAS  Google Scholar 

  30. Marti A, Corbalán MS, Forga L, Martinez JA, Hinney A, Hebebrand J . 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.

    Article  CAS  Google Scholar 

  31. Miraglia del Giudice E, Cirillo G, Nigro V, Santoro N, D'Urso L, Raimondo P et al. Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity. Int J Obes Relat Metab Disord 2002; 26: 647–651.

    Article  CAS  Google Scholar 

  32. Sina M, Hinney A, Ziegler A, Neupert T, Mayer H, Siegfried W et al. Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene. Am J Hum Genet 1999; 65: 1501–1507.

    Article  CAS  Google Scholar 

  33. Donohoue PA, Tao YX, Collins M, Yeo GSH, O'Rahilly S, Segaloff DL . Deletion of codons 88–92 of the melanocortin-4 receptor gene: a novel deleterious mutation in an obese female. J Clin Endocrinol Metab 2003; 88: 5841–5845.

    Article  CAS  Google Scholar 

  34. Valli-Jaakola K, Lipsanen-Nyman M, Oksanen L, Hollenberg AN, Kontula K, Bjørbaek C et al. Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese Finnish children and adults. J Clin Endocrinol Metab 2004; 89: 940–945.

    Article  CAS  Google Scholar 

  35. Geller F, Reichwald K, Dempfle A, Illig T, Vollmert C, Herpertz S et al. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am J Hum Genet 2004; 74: 572–581.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by a BOF-grant from the University of Antwerp to LVG and WVH and by a grant from the FWO-Flanders to LVG and WVH.

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Authors and Affiliations

  1. Department of Medical Genetics, University and University Hospital Antwerp, Wilrijk, Belgium

    S Beckers, A Peeters & W Van Hul

  2. Department of Diabetology, Metabolism and Clinical Nutrition, University Hospital Antwerp, Edegem, Belgium

    I Mertens & L Van Gaal

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  1. S Beckers
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  2. I Mertens
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  4. L Van Gaal
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Correspondence to W Van Hul.

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Beckers, S., Mertens, I., Peeters, A. et al. Screening for melanocortin-4 receptor mutations in a cohort of Belgian morbidly obese adults and children. Int J Obes 30, 221–225 (2006). https://doi.org/10.1038/sj.ijo.0803126

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  • DOI: https://doi.org/10.1038/sj.ijo.0803126

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