Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees
Fanny Stutzmann 1 ,
Karen Tan 2 ,
Vincent Vatin 1 ,
Christian Dina 1 ,
Béatrice Jouret 3 ,
Jean Tichet 4 ,
Beverley Balkau 5 ,
Natascha Potoczna 6 ,
Fritz Horber 6 ,
Stephen O'Rahilly 2 ,
I. Sadaf Farooqi 2 ,
Philippe Froguel 1 7 and
David Meyre 1
1 Centre National de la Recherche Scientifique-8090, Institute of Biology, Pasteur Institute, Lille, France
2 University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge,
U.K
3 Institut National de la Santé et de la Recherche Médicale U563, Children's Hospital, Toulouse, France
4 Institut inter Régional pour la Santé, La Riche, France
5 Institut National de la Santé et de la Recherche Médicale U780-IFR69, Villejuif, Université Paris-Sud, Orsay, France
6 Klinik Lindberg, Winterthur, and University of Berne, Berne, Switzerland
7 Department of Genomic Medicine, Hammersmith Hospital, Imperial College London, London, U.K
Corresponding author: Philippe Froguel, p.froguel{at}imperial.ac.uk
Abstract
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.
RESEARCH DESIGN AND 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 × 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.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 16 June 2008.
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Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees

10.2337/db08-0153