title: A novel MC4R deletion coexisting with FTO and MC1R gene variants, causes severe early onset obesity.
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.
  
  
  METHODS
  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, MC1Rand for the knownFTOsingle nucleotide polymorphism (SNP) rs9939609was 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 FTOrs9939609SNP. Finally, the identification of the known p.Arg160Trp MC1Rvariant in the patient accounts for the red hair and pale skin phenotypic features.
  
  
  CONCLUSIONS
  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 FTOrs9939609 SNP may worsen the phenotype.
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
authors.forename: Vassos
authors.initials: V
authors.lastname: Neocleous
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
authors.forename: Christos
authors.initials: C
authors.lastname: Shammas
authors.affiliation: Department of Biochemistry NMR Centre for Structural Biology, University of Liverpool, Institute of Integrative Biology, Crown Street, Liverpool, UK.
authors.forename: Marie M
authors.initials: MM
authors.lastname: Phelan
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
authors.forename: Pavlos
authors.initials: P
authors.lastname: Fanis
authors.affiliation: Department of Pharmacy and Department of Nursing, School of Health Sciences, Frederick University, Nicosia, Cyprus.
authors.forename: Maria
authors.initials: M
authors.lastname: Pantelidou
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.|Division of Pediatric Endocrinology, Paedi Center for specialized Pediatrics, Nicosia, Cyprus.|St George's University of London Medical School at the University of Nicosia, Nicosia, Cyprus.
authors.forename: Nicos
authors.initials: N
authors.lastname: Skordis
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, USA.
authors.forename: Christos
authors.initials: C
authors.lastname: Mantzoros
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
authors.forename: Leonidas A
authors.initials: LA
authors.lastname: Phylactou
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. meropitoumba@gmail.com.|Paediatrics & Paediatric Endocrinology Clinic, IASIS Hospital, 8036, Paphos, Cyprus. meropitoumba@gmail.com.
authors.forename: Meropi
authors.initials: M
authors.lastname: Toumba
mesh_terms: D017668:Age of Onset; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000378:metabolism*; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D005247:Feeding Behavior; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006200:Hair Color / Q000235:genetics; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D006963:Hyperphagia / Q000235:genetics / Q000503:physiopathology; D063766:Pediatric Obesity / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D012880:Skin Pigmentation / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: C470072:MC4R protein, human; D044102:Receptor, Melanocortin, Type 1; D044105:Receptor, Melanocortin, Type 4; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human