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Licensed Unlicensed Requires Authentication Published by De Gruyter August 5, 2015

The prevalence of melanocortin-4 receptor gene mutations in Slovak obese children and adolescents

  • Emil Polák EMAIL logo , Eva Vitáriušová , Peter Celec , Zuzana Pribilincová , Ľudmila Košťálová , Anna Hlavatá , László Kovács and Ľudevít Kádaši


Melanocortin-4 receptor (MC4R) deficiency is the most frequent monogenic form of obesity. The contribution of MC4R mutations to the Slovak population has not been investigated as yet. We screened the coding sequence of the MC4R gene in a cohort of 210 Slovak obese children and adolescents. We identified four different mutations in four patients, giving a mutation detection rate of 0.95%. Of these, three were missense mutations previously identified and characterized by other research groups (p.R7C, p.S127L and p. R305W, respectively). One was a novel nonsense mutation p.W174* detected in a severely obese 7-year-old boy. This mutation was further analyzed in family segregation analysis and exhibited variable penetrance. Two known amino acid polymorphisms (p.V103I and p.I251L) were also identified in seven subjects of our cohort group. We also performed multifactorial statistical analysis to determine the influence of genotypes on standard biochemical blood markers. No significant influence was observed in carriers of DNA variants on tested parameters. We conclude that rare heterozygous MC4R mutations contribute to the onset of obesity only in a few cases in the Slovak population.

Corresponding author: Emil Polák, Faculty of Natural Sciences, Department of Molecular Biology, Comenius University, Mlynska dolina B2-210, 842 15 Bratislava, Slovak Republic, Phone: +421260296653, Fax: +421260296508, E-mail: ; and Institute of Molecular Physiology and Genetics, Slovak Academy of Science, Bratislava, Slovakia
aEmil Polák and Eva Vitáriušová: These authors contributed to this work equally.


We would like to thank all the children and their families for their participation in this study. We are also grateful to pediatric endocrinologists Mária Kúseková MD†, Ľubica Tichá MD, Mária Ševecová MD, Adriana Dankovčíková MD, Marianna Debreová MD and Vilja Šandriková MD for their assistance in this study. This contribution is the result of projects implemented in the grants “Diagnostics of Socially Important Disorders in Slovakia, Based on Modern Biotechnologies” ITMS 26240220058 and “Creating Competitive Centre for research and development in the field of molecular medicine” ITMS 26240220071, supported by the Research and Developmental Operational Program funded by the ERDF. This work was also supported by VEGA 1/0497/08.

Conflict of interest: The authors declare no conflict of interest.


1. Ebbeling CB, Pawlak DB, Ludwig DS. Childhood obesity: public-health crisis, common sense cure. Lancet 2002;360:473–82.10.1016/S0140-6736(02)09678-2Search in Google Scholar

2. Moss A, Klenk J, Simon K, Thaiss H, Reinehr T, et al. Declining prevalence rates for overweight and obesity in German children starting school. Eur J Pediatr 2012;171:289–99.10.1007/s00431-011-1531-5Search in Google Scholar PubMed

3. Sedej K, Kotnik P, Avbelj Stefanija M, Groselj U, Sirca Campa A, et al. Decreased prevalence of hypercholesterolaemia and stabilisation of obesity trends in 5-year-old children: possible effects of changed public health policies. Eur J Endocrinol 2014;170:293–300.10.1530/EJE-13-0566Search in Google Scholar PubMed

4. Lee YS. Melanocortin 3 receptor gene and melanocortin 4 receptor gene mutations: the Asian Perspective. Diabetes Metab Res Rev 2012;28(Suppl 2):26–31.10.1002/dmrr.2351Search in Google Scholar PubMed

5. Hinney A, Schmidt A, Nottebom K, Heibult O, Becker I, 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;84:1483–6.10.1210/jcem.84.4.5728Search in Google Scholar PubMed

6. Krude H, Biebermann H, Luck W, Horn R, Brabant G, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998;19:155–7.10.1038/509Search in Google Scholar PubMed

7. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903–8.10.1038/43185Search in Google Scholar PubMed

8. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997;16:303–6.10.1038/ng0797-303Search in Google Scholar PubMed

9. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398–401.10.1038/32911Search in Google Scholar PubMed

10. Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 1998;20:113–4.10.1038/2407Search in Google Scholar PubMed

11. Apalasamy YD, Mohamed Z. Obesity and genomics: role of technology in unraveling the complex genetic architecture of obesity. Hum Genet 2015;134:361–74.10.1007/s00439-015-1533-xSearch in Google Scholar

12. Van der Ploeg LH, Martin WJ, Howard AD, Nargund RP, Austin CP, et al. A role for the melanocortin 4 receptor in sexual function. Proc Natl Acad Sci USA 2002;99:11381–6.10.1073/pnas.172378699Search in Google Scholar

13. Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004;116:337–50.10.1016/S0092-8674(03)01081-XSearch in Google Scholar

14. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997;88:131–41.10.1016/S0092-8674(00)81865-6Search in Google Scholar

15. Hainerova I, Larsen LH, Holst B, Finkova M, Hainer V, et al. Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis. J Clin Endocrinol Metab 2007;92:3689–96.10.1210/jc.2007-0352Search in Google Scholar PubMed

16. Stutzmann F, Tan K, Vatin V, Dina C, Jouret B, et al. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes 2008;57:2511–8.10.2337/db08-0153Search in Google Scholar PubMed PubMed Central

17. Hinney A, Bettecken T, Tarnow P, Brumm H, Reichwald K, et al. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. J Clin Endocrinol Metab 2006;91:1761–9.10.1210/jc.2005-2056Search in Google Scholar PubMed

18. van den Berg L, van Beekum O, Heutink P, Felius BA, van de Heijning MP, et al. Melanocortin-4 receptor gene mutations in a Dutch cohort of obese children. Obesity 2011;19:604–11.10.1038/oby.2010.259Search in Google Scholar PubMed

19. Dempfle A, Hinney A, Heinzel-Gutenbrunner M, Raab M, Geller F, et al. Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index. J Med Genet 2004;41:795–800.10.1136/jmg.2004.018614Search in Google Scholar PubMed PubMed Central

20. Stutzmann F, Vatin V, Cauchi S, Morandi A, Jouret B, et al. Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. Hum Mol Genet 2007;16:1837–44.10.1093/hmg/ddm132Search in Google Scholar PubMed

21. Wang D, Ma J, Zhang S, Hinney A, Hebebrand J, et al. Association of the MC4R V103I polymorphism with obesity: a Chinese case-control study and meta-analysis in 55,195 individuals. Obesity 2010;18:573–9.10.1038/oby.2009.268Search in Google Scholar PubMed

22. Vitariusova E, Babinska K, Kost’alova L, Rosinsky J, Hlavata A, et al. Food intake, leisure time activities and the prevalence of obesity in schoolchildren in Slovakia. Cent Eur J Public Health 2010;18:192–7.10.21101/cejph.a3607Search in Google Scholar PubMed

23. Zimmet P, Alberti KG, Kaufman F, Tajima N, Silink M, et al. The metabolic syndrome in children and adolescents - an IDF consensus report. Pediatr Diabetes 2007;8:299–306.10.1111/j.1399-5448.2007.00271.xSearch in Google Scholar PubMed

24. Gahagan S, Silverstein J. Prevention and treatment of type 2 diabetes mellitus in children, with special emphasis on American Indian and Alaska Native children. American Academy of Pediatrics Committee on Native American Child Health, American Academy of Pediatrics Section on Endocrinology. Pediatrics 2003;112:e328.10.1542/peds.112.4.e328Search in Google Scholar PubMed

25. Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000;106:253–62.10.1172/JCI9238Search in Google Scholar PubMed PubMed Central

26. Calton MA, Ersoy BA, Zhang S, Kane JP, Malloy MJ, et al. Association of functionally significant Melanocortin-4 but not Melanocortin-3 receptor mutations with severe adult obesity in a large North American case-control study. Hum Mol Genet 2009;18:1140–7.10.1093/hmg/ddn431Search in Google Scholar PubMed PubMed Central

27. Lubrano-Berthelier C, Dubern B, Lacorte JM, Picard F, Shapiro A, et al. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating. J Clin Endocrinol Metab 2006;91:1811–8.10.1210/jc.2005-1411Search in Google Scholar PubMed

28. Santini F, Maffei M, Ceccarini G, Pelosini C, Scartabelli G, 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;89:904–8.10.1210/jc.2003-031175Search in Google Scholar PubMed

29. Nowacka-Woszuk J, Cieslak J, Skowronska B, Majewska KA, Stankiewicz W, et al. Missense mutations and polymorphisms of the MC4R gene in Polish obese children and adolescents in relation to the relative body mass index. J Appl Genet 2011;52:319–23.10.1007/s13353-011-0036-2Search in Google Scholar PubMed PubMed Central

30. Melchior C, Schulz A, Windholz J, Kiess W, Schoneberg T, et al. Clinical and functional relevance of melanocortin-4 receptor variants in obese German children. Horm Res Paediatr 2012;78:237–46.10.1159/000343816Search in Google Scholar PubMed

31. Valli-Jaakola K, Palvimo JJ, Lipsanen-Nyman M, Salomaa V, Peltonen L, et al. A two-base deletion -439delGC in the melanocortin-4 receptor promoter associated with early-onset obesity. Horm Res 2006;66:61–9.10.1159/000093469Search in Google Scholar PubMed

32. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 2008;40:768–75.10.1038/ng.140Search in Google Scholar PubMed PubMed Central

33. Chambers JC, Elliott P, Zabaneh D, Zhang W, Li Y, et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet 2008;40:716–8.10.1038/ng.156Search in Google Scholar PubMed

34. Molou E, Schulpis KH, Birbilis C, Thodi G, Georgiou V, et al. Early screening of FTO and MC4R variants in newborns of Greek origin. J Pediatr Endocrinol Metab 2015;28:619–22.10.1515/jpem-2014-0320Search in Google Scholar PubMed

35. Srinivasan S, Lubrano-Berthelier C, Govaerts C, Picard F, Santiago P, et al. Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans. J Clin Invest 2004;114:1158–64.10.1172/JCI200421927Search in Google Scholar

36. Geller F, Reichwald K, Dempfle A, Illig T, Vollmert C, et al. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am J Hum Genet 2004;74:572–81.10.1086/382490Search in Google Scholar PubMed PubMed Central

37. Xiang Z, Litherland SA, Sorensen NB, Proneth B, Wood MS, et al. Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist. Biochemistry 2006;45:7277–88.10.1021/bi0600300Search in Google Scholar PubMed

38. Lubrano-Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, et al. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 2003;12:145–53.10.1093/hmg/ddg016Search in Google Scholar PubMed

39. Tao YX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev 2010;31:506–43.10.1210/er.2009-0037Search in Google Scholar PubMed PubMed Central

40. Melchior C, Kiess W, Dittrich K, Schulz A, Schoneberg T, et al. [Slim despite a genetic predisposition for obesity – -influence of environmental factors as chance? A case report]. Dtsch Med Wochenschr 2009;134:1047–50.10.1055/s-0029-1222565Search in Google Scholar PubMed

41. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003;348:1085–95.10.1056/NEJMoa022050Search in Google Scholar PubMed

Received: 2015-1-12
Accepted: 2015-4-24
Published Online: 2015-8-5
Published in Print: 2016-1-1

©2016 by De Gruyter

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