Binge eating as a major phenotype of melanocortin 4 receptor gene mutations.
BACKGROUND
Obesity, a multifactorial disease caused by the interaction of genetic factors with the environment, is largely polygenic. A few mutations in these genes, such as in the leptin receptor (LEPR) gene and melanocortin 4 receptor (MC4R) gene, have been identified as causes of monogenic obesity.


METHODS
We sequenced the complete MC4R coding region, the region of the proopiomelanocortin gene (POMC) encoding the alpha melanocyte-stimulating hormone, and the leptin-binding domain of LEPR in 469 severely obese white subjects (370 women and 99 men; mean [+/-SE] age, 41.0+/-0.5 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 44.1+/-2.0). Fifteen women and 10 men without a history of dieting or a family history of obesity served as normal-weight controls (age, 47.7+/-2.0 years; body-mass index, 21.6+/-0.4). Detailed phenotypic data, including information on body fat, resting energy expenditure, diet-induced thermogenesis, serum concentrations of leptin, and eating behavior, were collected.


RESULTS
Twenty-four obese subjects (5.1 percent) and one control subject (4 percent) had MC4R mutations, including five novel variants. Twenty of the 24 obese subjects with an MC4R mutation were matched for age, sex, and body-mass index with 120 of the 445 obese subjects without an MC4R mutation. All mutation carriers reported binge eating, as compared with 14.2 percent of obese subjects without mutations (P<0.001) and 0 percent of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers. No mutations were found in the region of POMC encoding alpha melanocyte-stimulating hormone.


CONCLUSIONS
Binge eating is a major phenotypic characteristic of subjects with a mutation in MC4R, a candidate gene for the control of eating behavior.
Branson
Ruth
R
Klinik Hirslanden, Zurich, Switzerland.
Potoczna
Natascha
N
Kral
John G
JG
Lentes
Klaus-Ulrich
KU
Hoehe
Margret R
MR
Horber
Fritz F
FF
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001481:Basal Metabolism; D001823:Body Composition; D002032:Bulimia / Q000235:genetics*; D016022:Case-Control Studies; D005247:Feeding Behavior; D005260:Female; D006579:Heterozygote; D006801:Humans; D020738:Leptin / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D044105:Receptor, Melanocortin, Type 4; D011956:Receptors, Cell Surface / Q000235:genetics; D018043:Receptors, Corticotropin / Q000172:deficiency / Q000235:genetics*; D054411:Receptors, Leptin; D000521:alpha-MSH / Q000235:genetics
D020738:Leptin; D044105:Receptor, Melanocortin, Type 4; D011956:Receptors, Cell Surface; D018043:Receptors, Corticotropin; D054411:Receptors, Leptin; D000521:alpha-MSH