title: Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity.
abstract: We initially performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls allowing for a case-control study. A total of 16 different missense, nonsense, and frameshift mutations were found in the obese study group; five of these have not been observed previously. In vitro assays revealed that nine [the haplotype (Y35X; D37V) was counted as one mutation] of the 16 mutations led to impaired cAMP responses, compared with wild-type receptor constructs. In contrast, only one novel missense mutation was detected in the controls, which did not alter receptor function. The association test based on functionally relevant mutations was positive (P = 0.006, Fisher's exact test, one-sided). We proceeded by screening a total of 1040 parents of 520 of the aforementioned obese young index patients to perform transmission disequilibrium tests. The 11 parental carriers of functionally relevant mutations transmitted the mutation in 81.8% (P = 0.033; exact one-sided McNemar test). These results support the hypothesis that these MC4R mutations represent major gene effects for obesity.
authors.affiliation: Clinical Research Group, Department of Child and Adolescent Psychiatry, Philipps-University of Marburg, D-35039 Marburg, Germany. anke.hinney@med.uni-marburg.de
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
authors.forename: Sarah
authors.initials: S
authors.lastname: Hohmann
authors.forename: Frank
authors.initials: F
authors.lastname: Geller
authors.forename: Constanze
authors.initials: C
authors.lastname: Vogel
authors.forename: Claudia
authors.initials: C
authors.lastname: Hess
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Wermter
authors.forename: Britta
authors.initials: B
authors.lastname: Brokamp
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Siegfried
authors.forename: Helmut
authors.initials: H
authors.lastname: Remschmidt
authors.forename: Helmut
authors.initials: H
authors.lastname: Schäfer
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D000818:Animals; D001827:Body Height / Q000235:genetics / Q000502:physiology; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D019556:COS Cells; D016022:Case-Control Studies; D002648:Child; D002522:Chlorocebus aethiops; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009767:Obesity, Morbid / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D004247:DNA