Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees.
OBJECTIVE
Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown.


METHODS
We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations.


RESULTS
Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P = 6.9 x 10(-10)). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60% in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at >40 years).


CONCLUSIONS
We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an "obesogenic" environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.
Stutzmann
Fanny
F
Centre National de la Recherche Scientifique-8090, Institute of Biology, Pasteur Institute, Lille, France.
Tan
Karen
K
Vatin
Vincent
V
Dina
Christian
C
Jouret
Béatrice
B
Tichet
Jean
J
Balkau
Beverley
B
Potoczna
Natascha
N
Horber
Fritz
F
O'Rahilly
Stephen
S
Farooqi
I Sadaf
IS
Froguel
Philippe
P
Meyre
David
D
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D002648:Child; D005247:Feeding Behavior; D005260:Female; D006801:Humans; D006963:Hyperphagia / Q000208:ethnology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009765:Obesity / Q000208:ethnology* / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D015995:Prevalence; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency / Q000235:genetics*; D044465:White People / Q000235:genetics* / Q000706:statistics & numerical data*
C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4