A novel MC4R deletion coexisting with FTO and MC1R gene variants, causes severe early onset obesity

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 betabarrel. 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 HORMONES 2016, 15(3):445-452 Address for correspondence: Meropi Toumba, MD, Paediatrics & Paediatric Endocrinology Clinic, IASIS Hospital, 8036, Paphos, Cyprus; Tel: +357 26848484, Fax: +357 26848300, E-mail: [email protected] Received: 21-04-2016, Accepted: 25-05-2016 Case report 446 V. NEOCLEOUS ET AL