Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating.
BACKGROUND
Heterozygous mutations in the melanocortin-4 receptor (MC4R) gene are the most common monogenic form of severe obesity in children. There are conflicting reports regarding the prevalence, nature, and pathogenic effects of MC4R mutations in adults with severe late-onset obesity.


OBJECTIVE
Our objective was to determine the prevalence of MC4R mutations in a cohort of severely obese adults and to determine the clinical phenotype and the phenotype-genotype relationship within adult MC4R mutation carriers.


METHODS
We conducted an observational study at a referral center.


METHODS
Participants included 769 adult patients with body mass index of at least 35 kg/m(2) and 444 nonobese control individuals.


METHODS
There were no interventions.


METHODS
We assessed the prevalence of pathogenic MC4R mutations, functional characteristics of the detected mutations, phenotype, and phenotype-genotype relationship within mutation carriers.


RESULTS
The global prevalence of obesity-specific MC4R mutations was 2.6%, and the 95% confidence interval (CI(95)) was 1.5-3.7. The prevalence of MC4R mutations was similar in patients developing obesity in childhood (2.83%; CI(95), 0.9-4.8) and in patients with a later onset of the disease (2.35%; CI(95), 0.9-3.8). Adult obese MC4R mutation carriers did not present with binge eating or with any specific clinical phenotype. The severity of the functional alterations of the mutated MC4Rs and in particular the intracellular retention of the receptor correlates both with the severity and the onset of the obesity in the mutation carriers.


CONCLUSIONS
Obese adult carriers of functionally relevant MC4R mutations do not specifically present with binge-eating disorder or a history of early-onset obesity. The onset and severity of the obesity in the carriers is related to the functional severity of the MC4R mutations.
Lubrano-Berthelier
Cecile
C
Diabetes Center and Department of Medicine, University of California San Francisco, San Francisco, California 94143-0573, USA.
Dubern
Beatrice
B
Lacorte
Jean-Marc
JM
Picard
Franck
F
Shapiro
Astrid
A
Zhang
Sumei
S
Bertrais
Sandrine
S
Hercberg
Serge
S
Basdevant
Arnaud
A
Clement
Karine
K
Vaisse
Christian
C
D000328:Adult; D000595:Amino Acid Sequence; D015992:Body Mass Index; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D001068:Feeding and Eating Disorders / Q000235:genetics* / Q000523:psychology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009765:Obesity / Q000453:epidemiology* / Q000235:genetics* / Q000523:psychology; D010641:Phenotype; D011446:Prospective Studies; D044105:Receptor, Melanocortin, Type 4 / Q000145:classification / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000521:alpha-MSH / Q000378:metabolism
D044105:Receptor, Melanocortin, Type 4; D011956:Receptors, Cell Surface; D000521:alpha-MSH; D004247:DNA