Identification of three novel genetic variants in the melanocortin-3 receptor of obese children.
The melanocortin-3 receptor (MC3R), a G-protein-coupled receptor expressed in the hypothalamus, is a key component of the leptin-melanocortin pathway that regulates energy homeostasis. It is suggested that an MC3R defect leads to an increased feed efficiency, by which nutrients are partitioned preferentially into fat. In this study, we hypothesized that early-onset obesity could be induced by mutations in MC3R. To investigate this hypothesis, we screened the entire coding region of the MC3R gene for mutations in obese subjects. A total of 404 overweight and obese children and adolescents, 86 severely obese adults (BMI ≥40 kg/m²), and 150 normal-weight control adults were included. Besides three synonymous coding variations in the MC3R gene (S69S, L95L, I226I), we were able to identify three novel heterozygous, nonsynonymous, coding mutations (N128S, V211I, L299V) in three unrelated obese children. None of these mutations were found in any of the control subjects. Functional studies assessing localization and signaling properties of the mutant receptors provided proof for impaired function of the L299V mutated receptor, whereas no conclusive evidence for functional impairment of the N128S and V211I mutated receptors could be established. First, these results provide supporting evidence for a role of the MC3R gene in the pathogenesis of obesity in a small subset of patients. Second, they show that caution is called for the interpretation of newly discovered mutations in MC3R.
Zegers
Doreen
D
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Beckers
Sigri
S
de Freitas
Fenna
F
Peeters
Armand V
AV
Mertens
Ilse L
IL
Verhulst
Stijn L
SL
Rooman
Raoul P
RP
Timmermans
Jean-Pierre
JP
Desager
Kristine N
KN
Massa
Guy
G
Van Gaal
Luc F
LF
Van Hul
Wim
W
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009765:Obesity / Q000235:genetics*; D009767:Obesity, Morbid / Q000235:genetics; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics*
D044104:Receptor, Melanocortin, Type 3