Background Melanocortin 4 receptor (MC4R) deficiency is thecommonest monogenic form of obesity. However, the clinical spectrumand mode of inheritance have not been defined, pathophysiologicalmechanisms leading to obesity are poorly understood, and thereis little information regarding genotype–phenotype correlations.
Methods We determined the nucleotide sequence of the MC4R genein 500 probands with severe childhood obesity. Family studieswere undertaken to examine cosegregation of identified mutationswith obesity. Subjects with MC4R deficiency underwent metabolicand endocrine evaluation; the results were correlated with thesignaling properties of mutant receptors.
Results Twenty-nine probands (5.8 percent) had mutations inMC4R; 23 were heterozygous, and 6 were homozygous. Mutationcarriers had severe obesity, increased lean mass, increasedlinear growth, hyperphagia, and severe hyperinsulinemia; homozygoteswere more severely affected than heterozygotes. Subjects withmutations retaining residual signaling capacity had a less severephenotype.
Conclusions Mutations in MC4R result in a distinct obesity syndromethat is inherited in a codominant manner. Mutations leadingto complete loss of function are associated with a more severephenotype. The correlation between the signaling propertiesof these mutant receptors and energy intake emphasizes the keyrole of this receptor in the control of eating behavior in humans.
Although changes in diet and exercise underlie the current globalincrease in the prevalence of obesity, there is considerableevidence of a substantial genetic contribution to the regulationof body weight.1 Causative mutations underlying several recognizablepleiotropic obesity syndromes (e.g., Bardet–Biedl syndrome)have recently been identified, but in no case has a clear mechanisticlink between the product of the mutant gene and disordered energybalance been clarified.2 Study of strains of genetically obesemice has resulted in the discovery of several genes, mutationsof which have subsequently been found to lead to severe humanobesity. Deficiency of the adipocyte-derived hormone leptinresults in obesity, hyperphagia, infertility, and impaired T-cell–mediatedimmunity in mice3,4 and humans,5,6 and the administration ofleptin completely reverses all aspects of the phenotype in bothspecies.7,8,9,10,11 Proopiomelanocortin is regulated by leptinand is cleaved by prohormone convertases to yield melanocyte-stimulatinghormone.12 Loss-of-function mutations in the proopiomelanocortingene lead to obesity in mice and humans.13,14 The actions of melanocyte-stimulating hormone on the melanocortin 4 receptor(MC4R) lead to a decrease in food intake,15 and mice with nullmutations in MC4R have increased food intake, obesity, and hyperinsulinemia.16
We and others have identified mutations in MC4R in obese subjects.17,18,19However, the lack of clinical information has precluded a thoroughdescription of the clinical syndrome or systematic examinationof correlations between the genotype and the phenotype. Therefore,we screened 500 subjects with severe, early-onset obesity formutations in MC4R and conducted clinical studies of those withmutations. We also characterized the in vitro function of mutantreceptors and examined relations between molecular and clinicalphenotypes.
Methods
Subjects
Subjects with severe obesity of early onset (before 10 yearsof age) were eligible for entry into the Genetics of ObesityStudy (GOOS) and are referred to as probands. We recruited 750subjects. Standard deviation scores for body-mass index (theweight in kilograms divided by the square of the height in meters)were calculated with the use of reference data from the UnitedKingdom population.20 Among the probands, the mean (±SD)standard-deviation score for body-mass index was 4.2±0.8.To date, the first consecutive 500 unrelated probands have beenexamined for mutations in MC4R. Subjects with mutations in MC4Rand their relatives were invited to the Wellcome Trust ClinicalResearch Facility at Addenbrooke's Hospital, Cambridge, UnitedKingdom.
All studies were approved by the Anglia and Oxford multiregionalethics committee. The clinical studies were performed afterapproval by the local–regional ethics committee of Cambridge.Each subject, or his or her parent in the case of children youngerthan 16 years, provided written informed consent (oral consentwas obtained from the minors themselves). All clinical studieswere conducted in accordance with the principles of the Declarationof Helsinki.
Detection of Mutations and Genotyping
Genomic DNA was isolated from whole-blood lymphocytes, and thecoding region of the MC4R gene was amplified by the polymerasechain reaction and sequenced as previously described.17 To determineallelic frequency, we determined the MC4R sequence in 100 allelesfrom nonobese control subjects from the United Kingdom who wererandomly selected from a local population-based cohort.21
Studies of Mutant Receptor Function
Wild-type (normal) and mutant MC4Rs were cloned into the mammalianexpression vector pcDNA3 (Invitrogen) as previously reported17and transiently transfected into HEK293 cells with a luciferasereporter under the control of a promoter that was responsiveto cyclic AMP (cAMP),22 according to the manufacturer's protocols(Fugene Reagent, Roche Diagnostics). All transfections incorporateda pRL-CMV plasmid (Promega), which constitutively expressesRenilla luciferase and controls for the efficiency of transfection.Cells were deprived of serum, and various concentrations of melanocyte-stimulating hormone (Bachem) were added. After thecells were harvested, luciferase activity was determined witha luciferase assay system (Promega). Activation of MC4R increasesintracellular cAMP, which stimulates the expression of luciferase.Each experiment was conducted in quadruplicate; values are givenas means ±SE. Data were analyzed and curves were fittedwith the use of Origin software (OriginLab).
Body Composition, Growth, and Energy Balance
Anthropometry and whole-body dual-energy x-ray absorptiometryto determine body composition were performed as previously described.17Bone mineral density z scores were calculated with use of thedata set of the third National Health and Nutrition ExaminationSurvey.23 The subjects' resting metabolic rate was measuredby indirect calorimetry17 after they had slept for eight hoursat the clinical research facility. After adjustment for bodycomposition, the resting metabolic rate was compared with thatpredicted according to age- and sex-specific equations.24,25Semiquantitative assessment of eating behavior was undertakenin children under 16 years of age. The children were given a4300-kcal meal at breakfast after an overnight fast, the contentswere covertly weighed before the meal and after the childrenfinished eating, and total energy intake and nutrient compositionwere calculated.10 Energy intake was expressed per kilogramof lean body weight as a simple means of comparing intake amongsubjects of different ages and body sizes, since no method ofadjustment for age or sex has been validated.
Metabolic and Endocrine Studies
Blood samples obtained while the subjects were fasting wereanalyzed for leptin, lipids, glucose, insulin, thyrotropin,free thyroxine, corticotropin, insulin-like growth factor I,follicle-stimulating hormone, luteinizing hormone, estradiol,and testosterone with the use of standard assays. In addition,24-hour urine free cortisol was measured in some subjects.
Statistical Analysis
Clinical data are expressed as means ±SD, and in vitrodata are expressed as means ±SE. Differences betweengroups were compared with use of the unpaired Student's t-test.All reported P values are two-sided. P values of less than 0.05were considered to indicate statistical significance.
Results
Detection of Mutations and Functional Analysis
We identified mutations in 29 of the 500 probands (5.8 percent)that were not found in 100 alleles from randomly selected nonobesesubjects (Figure 1A). Three variants — V103I, I251L, andT112M — were found in obese and control subjects; thesevariants have been shown to have no effect on MC4R signalingand were not studied further. Signaling properties of mutantreceptors were examined (Figure 1B). Whereas all of the frame-shiftmutations and some of the missense mutations resulted in completeloss of signaling, some of the missense mutations encoded receptorswith residual ability to generate cAMP in response to ligand(Figure 1B and Table 1).
Figure 1. Mutations in the Melanocortin 4 Receptor (MC4R) Gene (Panel A) and in Vitro Function (Panel B).
Panel A shows the positions of the 24 different mutations and sequence variants identified. Mutations found in heterozygous form in obese probands are shown in orange, and mutations found in homozygous form in obese probands are shown in green. Some mutations were found in more than one proband, and the number of probands identified is indicated. Shown in blue are common sequence variants not considered to be of pathogenic importance. Panel B shows the mean (±SE) response of mutant and wild-type MC4Rs to the addition of increasing amounts of ligand, melanocyte-stimulating hormone, shown on a logarithmic scale, in a cAMP-responsive luciferase reporter assay
Table 1. Mutations in the Melanocortin 4 Receptor (MC4R) Gene Associated with Severe Obesity in Childhood and Loss of Function in Vitro.
Mode of Inheritance
All relatives of the probands were genotyped at MC4R by directnucleotide sequencing. MC4R mutations identified in heterozygousprobands segregated with early-onset obesity with 100 percentpenetrance (Figure 2A). In six families the proband was homozygousfor a mutation in MC4R (Figure 2B), including one (Family 12)in which the proband appeared to be homozygous for a deletionof MC4R. In these families all 12 homozygotes became severelyobese at an early age; in contrast, the prevalence of early-onsetobesity was only 68 percent among heterozygous subjects (17of 25). Heterozygotes from these families were less obese thantheir homozygous relatives, as indicated by mean (±SD)body-mass index standard-deviation scores of 1.92±1.6and 4.64±1.2, respectively (P=0.001). These findingsindicate that the obesity resulting from mutations in MC4R isassociated with a codominant mode of inheritance.
Figure 2. Pedigrees of 11 Families with a Proband Who Was Heterozygous for a Melanocortin 4 Receptor (MC4R) Mutation (Panel A) and 6 Families with a Homozygous Proband (Panel B).
Pedigrees are shown for the 17 families in which family members were available for genotyping. Squares denote male family members; circles female family members; slashes family members who have died; open symbols unaffected family members; and solid symbols family members with early-onset obesity, defined as weight above the 98th percentile and onset of obesity before 10 years of age; and arrows indicate the proband in each family. Known genotypes are indicated below each symbol: minus signs indicate mutations in MC4R on one allele, and plus signs indicate a normal MC4R genotype on one allele; thus, heterozygotes are depicted as +/–, and homozygotes as –/–. In two cousins in Family 12 (indicated by the asterisks), the MC4R gene could neither be amplified by the polymerase chain reaction nor detected by Southern blotting; they are likely to be homozygous for a null mutation in MC4R and were included as such in the phenotypic studies, as were their consanguineous parents, who are presumed to be heterozygous for a deletion of MC4R.
Clinical Phenotype of MC4R Deficiency
Clinical Presentation, Body Composition, and Growth
The clinical phenotype of MC4R deficiency was studied in 12probands and 39 of their relatives with early-onset obesitywho had mutations in MC4R. This group consisted of 42 heterozygotesand 9 homozygotes. The mean body-mass index standard-deviationscore for the 51 subjects was 3.14±1.61, with a meanscore of 2.79±1.38 among heterozygotes and 4.81±1.63among homozygotes. Body weight deviated from predicted UnitedKingdom reference percentiles in the first year of life in over80 percent of those for whom early growth charts were available(Figure 3A). At all ages, but particularly during the firstfive years, the standard-deviation scores for height of childrenwith MC4R deficiency were greater than those of obese childrenwithout MC4R mutations (Figure 3B). Serum concentrations ofinsulin-like growth factor I were appropriate for age in allinstances (data not shown).
Figure 3. Growth (Panels A and B) and Body Composition (Panel C) in Subjects with Melanocortin 4 Receptor (MC4R) Deficiency.
Panel A shows growth charts for two children with MC4R deficiency during the first year of life, as compared with normal reference values in the United Kingdom (2nd, 50th, and 98th percentiles). Panel B shows mean (±SD) standard-deviation scores for height at different ages in subjects with MC4R deficiency and obese subjects with a normal MC4R genotype who were matched for age and body-mass index. Panel C shows a 9-year-old boy who was homozygous for a mutation in MC4R (left-hand side) and his 16-year-old brother, who had a normal genotype (right-hand side).
Dual-energy x-ray absorptiometry was used to examine body compositionin 48 subjects. Although the mean percentage of body fat amongcarriers of MC4R mutations was clearly abnormal at 42.9±8.6percent (normal range, 15 to 25), the relative contributionof fat-free mass to overall weight was greater in these subjectsthan in subjects with leptin deficiency who had a similar body-massindex (mean fat mass, 57.0 percent).11 Thus, MC4R deficiencyis characterized by an increase in both fat and lean mass. Homozygoteshad a higher mean percentage of body fat than heterozygotes(49.5±4.7 percent vs. 41.6±6.6 percent, P=0.01).The characteristic appearance of a child with MC4R deficiency— severely obese and tall, with increased fat-free massas well as fat mass — is illustrated in Figure 3C.
We have previously reported that subjects with MC4R deficiencyhave increased bone mineral density and bone mineral content.17These extended clinical studies confirmed those observations:37 of 44 subjects with MC4R deficiency (84 percent) had a bonemineral density z score of more than 1 (mean, 1.7±0.9).
Energy Balance
All subjects had a history of increased appetite, particularlyin childhood. The energy consumed by carriers of MC4R mutationsat an ad libitum meal was three times that of their unaffectedsiblings, after adjustment for lean body mass (mean, 36.4±8.4kcal per kilogram of lean mass vs. 11±1.9 kcal per kilogramof lean mass; P=0.001). In general, older children (those 11to 15 years of age) were less hyperphagic and ate less at thetest meal (Figure 4A). The resting metabolic rate of subjectswith MC4R mutations was similar to that predicted on the basisof age- and sex-specific equations after correction for leanbody mass (r2=0.84 for adults, r2=0.94 for boys, and r2=0.70for girls) (see Supplementary Appendix 1 and Supplementary Appendix 2,available with the full text of this article at http://www.nejm.org).
Figure 4. Effects of Age and in Vitro Function of the Mutant Melanocortin 4 Receptor (MC4R) on Mean (±SD) ad Libitum Energy Intake (Panels A and C) and Plasma Insulin Concentrations (Panel B).
Panel A shows the ad libitum energy intake at a 4300-kcal test meal in subjects with MC4R deficiency at different ages. Only data for subjects who were heterozygous for MC4R mutations resulting in complete loss of function are shown. Panel B shows plasma insulin concentrations in subjects with MC4R deficiency at different ages, as compared with subjects from the cohort with a normal MC4R genotype who were matched for age, sex, and body-mass index standard-deviation scores. Panel C shows the mean energy intake at a 4300-kcal test meal (adjusted for lean body weight in kilograms) in subjects who were heterozygous for MC4R mutations resulting in complete or partial loss of function in vitro. Mean energy intake in two children with leptin deficiency (before and after treatment) and in family members with no mutations at the MC4R locus is shown for comparison. It is not possible to match subjects with leptin deficiency for age with subjects who have MC4R deficiency, since only four subjects with leptin deficiency have been described to date, two of whom were studied here; there appears to be no age-related change in food intake in leptin deficiency.11
Metabolic and Endocrine Function
All subjects with MC4R deficiency were euglycemic, but plasmainsulin concentrations were significantly elevated as comparedwith those in obese subjects matched for age, standard-deviationscore for body-mass index, and sex who did not have MC4R mutations(Figure 4B). There was also an age-dependent effect: childrenhad higher plasma insulin concentrations than adults with MC4Rdeficiency (data not shown).
Serum lipid concentrations and urinary 24-hour free cortisolexcretion were within normal ranges, and serum leptin concentrationswere appropriate for fat mass (data not shown). All subjectshad free thyroxine concentrations in the normal range. Foursubjects had a slight elevation in thyrotropin, and one a subnormalconcentration of thyrotropin (see Supplementary Appendix 3,available with the full text of this article at http://www.nejm.org).Gonadotropin secretion, concentrations of sex steroids, andsecondary sexual characteristics were appropriate for age inaffected children (data not shown). None of the adults reporteda history of infertility, males did not report decreased erectilefunction or decreased libido, and all females of reproductiveage had regular menstrual cycles.
Relation between Genotype and Clinical Phenotype
To examine whether functional properties of particular mutantMC4Rs might influence the clinical phenotype, standard-deviationscores for body-mass index and height, energy intake at thetest meal, and fasting plasma insulin concentrations were comparedin subjects with complete loss of function of MC4R and thosewith a partial loss of function. Since the phenotype appearsto change with age, only children (those younger than 16 years)were compared. The 23 subjects who were heterozygous for nonfunctionalmutant receptors were more obese than the 22 with partiallyfunctioning mutant receptors (body-mass index standard-deviationscore, 3.3±1.1 vs. 1.9±1.3; P=0.005). For eachphenotype, subjects with a mutation resulting in complete lossof function in vitro were more severely affected (Table 2).For variables that did not appear to be affected by MC4R deficiency,such as resting metabolic rate per kilogram of lean mass, therewas no correlation between genotype and phenotype. Figure 4Cshows the results of the test meal in heterozygotes with partiallyfunctioning receptors and those with inactive receptors; forcomparison, results are also shown for two children with congenitalleptin deficiency before and after leptin therapy.
Table 2. Correlations between Genotype and Phenotype in Children with Melanocortin 4 Receptor (MC4R) Deficiency.
Discussion
In this large study, we found that 5.8 percent of subjects withsevere obesity commencing in childhood had pathogenic mutationsin MC4R. Thus, MC4R deficiency represents the commonest knownmonogenic obesity disorder. The lower prevalence reported insome studies may be explained by the differences in prevalencein certain ethnic groups,26 but it may also reflect the lateronset and reduced severity of obesity of subjects in these studies.27The great majority of subjects thus far described have beenheterozygotes, with only one homozygote17 and one compound heterozygote18reported. We identified five additional homozygous probands,allowing us to examine the mode of inheritance in a more detailedmanner. We found complete penetrance of early-onset obesityin heterozygous probands and found that homozygous probandswere more obese than heterozygotes in these families. Thus,codominance is the most appropriate descriptor for the modeof inheritance, a finding supported by the pattern of inheritanceof obesity seen in heterozygous and homozygous Mc4r knockoutmice.
However, although all homozygotes in the families of homozygousprobands were severely obese, only 68 percent of heterozygoteswere obese, differences that cannot be explained by the in vitrofunction of these mutations. Since all homozygous probands wereof Indo–European origin, the penetrance of MC4R mutationsmay vary in different ethnic groups. Given the large numberof potential influences on body weight, it is not surprisingthat genetic and environmental modifiers will have major effectsin some pedigrees. Such effects may also explain differencesin the severity of the clinical phenotype observed in otherpopulations.
MC4R deficiency is characterized by an increase in lean bodymass and bone mineral density, increased linear growth, hyperphagia,and severe hyperinsulinemia. Most of these features are seenin Mc4r knockout mice, suggesting the preservation of the relevantmelanocortin pathways between rodents and humans. We confirmedthat ad libitum energy intake was greatly increased in childrenwith MC4R deficiency as compared with their unaffected siblings.This finding was consistent with their reported food-seekingbehavior in the free-living situation. However, all subjectswith MC4R deficiency, including those who were homozygous fora deletion of MC4R, had a lower ad libitum food intake thanthose with leptin deficiency (Figure 4C), suggesting that someof the inhibitory effects of leptin on food intake may be mediatedby other neuropeptides.
We found no evidence of a major deficit in basal energy expenditurein subjects with MC4R deficiency, although Mc4r knockout micehave a 10 percent reduction in basal oxygen consumption.28 Thismay reflect a true species difference or subtle defects in humanenergy expenditure, which may be detectable only when energyhomeostasis is perturbed. In Mc4r knockout mice, overfeedingwith a high-fat diet leads to increased feed efficiency andis associated with a failure to increase diet-induced thermogenesis,suggesting that MC4R has a key role in adaptive thermogenesis.29
All obese subjects with MC4R deficiency had severe hyperinsulinemia.Severe hyperinsulinemia, which appears before the onset of hyperphagiaor obesity in Mc4r knockout mice, can be blocked by the administrationof an -adrenergic blocker, suggesting a role for the centralmelanocortin pathways in activating sympathetic drive to thepancreas.30,31 Whether MC4R directly regulates insulin secretionin humans is yet to be determined. The severe, early hyperinsulinemiamay contribute to the increased linear growth associated withMC4R deficiency, since no evidence of excessive secretion ofgrowth hormone has been found in either rodents or humans.
The development of puberty and fertility were normal in subjectswith MC4R deficiency, in contrast to findings in obese subjectswith mutations in leptin, leptin receptor, or PC-1,6,32,33 suggestingthat the effects of leptin on reproductive function are notmediated by MC4R. Male subjects with MC4R deficiency did notreport decreased erectile function, whereas pharmacologic MC4Ractivation in mice has been reported to increase erections andsexual behavior.34 We found no clear evidence of an effect onthe thyroid axis, which is consistent with the normal thyroidfunction of Mc4r knockout mice.16
There was an age-related decrease in hyperinsulinemia, whichparallels the apparent amelioration of hyperphagia that seemsto occur with adulthood in these subjects. As yet there is noexplanation for our observation that the phenotype becomes lessprominent with age.
Finally, we found evidence of a correlation between the in vitrofunction of mutant MC4Rs and the severity of the clinical phenotype.All aspects of the phenotype were more severe in those withcomplete loss as opposed to partial loss of function of MC4R,and this finding appeared to be consistent for both heterozygotesand homozygotes. Our findings suggest that the regulation ofbody weight in humans is sensitive to variations in the amountof functional MC4R. The correlation between the in vitro propertiesof a neuropeptide receptor and a measure of a complex humanbehavior such as food intake is striking and perhaps unique.Our data provide compelling confirmation of the critical roleof MC4R in the control of eating behavior and fat mass in humans.
Supported by grants from the Wellcome Trust (to Drs. Farooqiand O'Rahilly) and the Medical Research Council (to Dr. O'Rahilly)and by an unconditional grant from Merck Pharmaceuticals tosupport patient studies.
We are indebted to the patients and their families for theirparticipation.
Source Information
From the Genetics of Obesity Collaborative Group (T.C.) and the University Departments of Medicine and Clinical Biochemistry (I.S.F., J.M.K., G.H.S.Y., E.J.L., S.O.'R.), Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
Address reprint requests to Dr. O'Rahilly at the Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom, or at sorahill{at}hgmp.mrc.ac.uk.
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Appendix
Other members of the Genetics of Obesity Collaborative Groupare as follows: Drs. R. Stanhope, B. Houlsby, D. Matthews, P.Clayton, E. Crowne, R. Cooke, N. Lingham, B. Adler, M. Rossitor,S. Shakil, S. Sawhney, B. Nauriah, and G. Butler.
Bouchard, C.
(2009). Childhood obesity: are genetic differences involved?. Am. J. Clin. Nutr.
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Chan, L. F., Webb, T. R., Chung, T.-T., Meimaridou, E., Cooray, S. N., Guasti, L., Chapple, J. P., Egertova, M., Elphick, M. R., Cheetham, M. E., Metherell, L. A., Clark, A. J. L.
(2009). MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. Proc. Natl. Acad. Sci. USA
106: 6146-6151
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Peter, J.-C., Bekel, A., Lecourt, A.-C., Zipfel, G., Eftekhari, P., Nesslinger, M., Breidert, M., Muller, S., Kessler, L., Hofbauer, K. G.
(2009). Anti-Melanocortin-4 Receptor Autoantibodies in Obesity. J. Clin. Endocrinol. Metab.
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Friedman, J. M
(2009). Leptin at 14 y of age: an ongoing story. Am. J. Clin. Nutr.
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Haskell-Luevano, C., Schaub, J. W., Andreasen, A., Haskell, K. R., Moore, M. C., Koerper, L. M., Rouzaud, F., Baker, H. V., Millard, W. J., Walter, G., Litherland, S. A., Xiang, Z.
(2009). Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse. FASEB J.
23: 642-655
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Hooper, L. M., Burnham, J. J., Richey, R.
(2009). Select Parent and Family System Correlates of Adolescent Current Weight Status: A Pilot Study. The Family Journal
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melanocyte-stimulating hormone.12 Loss-of-function mutations in the proopiomelanocortin gene lead to obesity in mice and humans.13,14 The actions of 
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