ESPE Abstracts (2015) 84 P-2-338

A Novel Melanocortin-4-Receptor Gene Mutation Associated with Early Onset Severe Obesity

Meropi Toumbaf, Christos Shammasa, Vassos Neocleousa, Marie Phelanb, Nicos Skordisc,d, Leonidas Phylactoua & Christos Mantzorose


aDepartment of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; bDepartment of Biochemistry, Institute of Integrative Biology, NMR Centre for Structural Biology, University of Liverpool, Liverpool, UK; cDivision of Pediatric Endocrinology, Paedi Center for specialized Pediatrics, Nicosia, Cyprus; dSt George’s University of London Medical School, University of Nicosia, Nicosia, Cyprus; eDivision of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; fDepartment of Paediatrics, Iasis Hospital, Paphos, Cyprus


Background: The melanocortin-4-receptor gene (MC4R) is a key regulator for appetite and satiety. MC4R mutations account for 6–8% of severe obesity in children with variable expression and penetrance.

Case presentation: A 3-year-old girl is presented with severe early onset and progressive obesity. She was born full-term with appropriate of gestational age weight by non-consanguineous parents. She had normal psychomotor milestones and no syndromic features but her red-brown hair was characteristic. Her BMI at presentation was 30 kg/m2 (+4.5 SDS) and her waist circumference was 81 cm (+6.1 SDS). She exhibited a remarkably increased linear growth with bone age advancement by 2 years and no signs of pubarche. At the age of 5 years (BMI 29.6 kg/m2, +3.2 SDS) despite her effort with a healthy lifestyle, she developed hyperinsulinaemia and was commenced on treatment with metformin. A novel heterozygous mutation MC4R p.M215del (c.643_645delATG) deletion was found on the patient and her father who was also obese (BMI 33 kg/m2). 3D structural dynamic simulation studies have been used to investigate the conformational changes induced by this novel amino acid deletion. Additionally, the in silico software package ‘Mutation Taster’ was used to predict the pathogenicity of p.M215del deletion and identified it as a disease causing mutation.

Conclusion: The deletion of methionine at position 215 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 obesity phenotype especially with additional negative effect of environmental factors and unhealthy lifestyle habits even in heterozygote patients.

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