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.
Ebbeling CB, Pawlak DB, Ludwig DS. Childhood obesity: public-health crisis, common sense cure. Lancet 2002;360:473–82.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Apalasamy YD, Mohamed Z. Obesity and genomics: role of technology in unraveling the complex genetic architecture of obesity. Hum Genet 2015;134:361–74.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Tao YX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev 2010;31:506–43.
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.
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.
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.
The Journal of Pediatric Endocrinology and Metabolism (JPEM) is the only international journal dedicated exclusively to endocrinology in the neonatal, pediatric and adolescent age groups, and publishes the results of clinical investigations in pediatric endocrinology and basic research. JPEM publishes Review Articles, Original Research, Case Reports, Short Communications and Letters to the Editor.