Abstract
OBJECTIVE: Heterozygous mutations on the melanocortin-4-receptor gene (MC4R) are the most frequent cause of monogenic obesity. We describe a novel MC4R deletion in a girl with severe early onset obesity, tall stature, pale skin and red hair. CASE REPORT: Clinical and hormonal parameters were evaluated in a girl born full-term by non-consanguineous parents. Her body mass index (BMI) at presentation (3 years) was 30 kg/m2 (z-score: +4.5SDS). By the age of 5.2 years, she exhibited extreme linear growth acceleration and developed hyperinsulinemia. METHODS: Direct sequencing of the MC4R, MC1R and for the known FTO single nucleotide polymorphism (SNP) rs9939609 was performed for the patient and her family. RESULTS: A novel heterozygous MC4R p.Met215del (c.643_645delATG) deletion was identified in the patient, her father and her brother, both of whom exhibited a milder phenotype. 3D structural dynamic simulation studies investigated the conformational changes induced by the p.Met215del. The patient and her mother were also found to be carriers of the obesity risk associated FTO rs9939609 SNP. Finally, the identification of the known p.Arg160Trp MC1R variant in the patient accounts for the red hair and pale skin phenotypic features. CONCLUSION: The p.Met215del causes global conformational and functional changes as it is localized at the alpha-helical transmembrane regions and the membrane spanning regions of the beta-barrel. This novel mutation produces a severe overgrowth phenotype that is apparent as from infancy and is progressive in childhood. The additional negative effect of environmental and unhealthy lifestyle habits as well as a possible co-interaction of FTO rs9939609 SNP may worsen the phenotype.
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References
Sabin MA, Werther GA, Kiess W, 2011 Genetics of obesity and overgrowth syndromes. Best Pract Res Clin Endocrinol Metab 25: 207–220.
Vaisse C, Clement K, Guy-Grand B, Froguel P, 1998 A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20: 113–114.
Tan K, Pogozheva ID, Yeo GS, et al, 2009 Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor. Endocrinology 150: 114–125.
Cone RD, Lu D, Koppula S, et al, 1996 The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res 51: 287–317; discussion 318.
Huszar D, Lynch CA, Fairchild-Huntress V, et al, 1997 Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131–141.
Farooqi IS, Keogh JM, Yeo GS, et al, 2003 Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348: 1085–1095.
Hardy R, Wills AK, Wong A, et al, 2010 Life course variations in the associations between FTO and MC4R gene variants and body size. Hum Mol Genet 19: 545–552.
Loos RJ, Lindgren CM, Li S, et al, 2008 Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40: 768–775.
Frayling TM, Timpson NJ, Weedon MN, et al, 2007 A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316: 889–894.
Dina C, Meyre D, Gallina S, et al, 2007 Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 39: 724–726.
Valverde P, Healy E, Sikkink S, et al, 1996 The Asp-84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma. Hum Mol Genet 5: 1663–1666.
Box NF, Wyeth JR, O’Gorman LE, Martin NG, Sturm RA, 1997 Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair. Hum Mol Genet 6: 1891–1897.
Scott MC, Wakamatsu K, Ito S, et al, 2002 Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation. J Cell Sci 115: 2349–2355.
Ellis C, Smith A, 2004 Highlighting the pitfalls and possibilities of drug research. Nat Rev Drug Discov 3: 238–278.
Lobstein T, Jackson-Leach R, Moodie ML, et al, 2015 Child and adolescent obesity: part of a bigger picture. Lancet 385: 2510–2520.
Albuquerque D, Stice E, Rodriguez-Lopez R, Manco L, Nobrega C, 2015 Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective. Mol Genet Genomics 290: 1191–1221.
Gantz I, Fong TM, 2003 The melanocortin system. Am J Physiol Endocrinol Metab 284: E468–474.
Yeo GS, Lank EJ, Farooqi IS, et al, 2003 Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet 12: 561–574.
Donohoue PA, Tao YX, Collins M, et al, 2003 Deletion of codons 88–92 of the melanocortin-4 receptor gene: a novel deleterious mutation in an obese female. J Clin Endocrinol Metab 88: 5841–5845.
Turner L, Gregory A, Twells L, Gregory D, Stavropoulos DJ, 2015 Deletion of the MC4R gene in a 9-year-old obese boy. Child Obes 11: 219–223.
Martinelli CE, Keogh JM, Greenfield JR, et al, 2011 Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion. J Clin Endocrinol Metab 96: E181–188.
Fan W, Dinulescu DM, Butler AA, et al, 2000 The central melanocortin system can directly regulate serum insulin levels. Endocrinology 141: 3072–3079.
Hakanen M, Raitakari OT, Lehtimaki T, et al, 2009 FTO genotype is associated with body mass index after the age of seven years but not with energy intake or leisure-time physical activity. J Clin Endocrinol Metab 94: 1281–1287.
Smith R, Healy E, Siddiqui S, et al, 1998 Melanocortin 1 receptor variants in an Irish population. J Invest Dermatol 111: 119–122.
Palmer JS, Duffy DL, Box NF, et al, 2000 Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am J Hum Genet 66: 176–186.
Stefanaki I, Panagiotou OA, Kodela E, et al, 2013 Replication and predictive value of SNPs associated with melanoma and pigmentation traits in a Southern European case-control study. PLoS One 8: e55712.
Beaumont KA, Newton RA, Smit DJ, et al, 2005 Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk. Hum Mol Genet 14: 2145–2154.
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Neocleous, V., Shammas, C., Phelan, M.M. et al. A novel MC4R deletion coexisting with FTO and MC1R gene variants, causes severe early onset obesity. Hormones 15, 445–452 (2016). https://doi.org/10.14310/horm.2002.1686
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DOI: https://doi.org/10.14310/horm.2002.1686