Body Mass Index Quantitative Trait Locus 20

A number sign (#) is used with this entry because of evidence that heterozygous or homozygous loss-of-function mutations in the melanocortin-4 receptor gene (MC4R; 155541) cause obesity (BMIQ20), whereas MC4R gain-of-function mutations are associated with resistance to obesity.

Description

Obesity due to mutation in the MC4R gene is the most common cause of monogenic obesity. Patients have early-onset severe obesity and hyperphagia (Farooqi et al., 2003).

Clinical Features

Yeo et al. (1998) described a 4-year-old boy, born to nonconsanguineous parents, with severe obesity in whom no evidence for a recognized clinical syndrome or a structural hypothalamic cause of the obesity was found. Although the boy's birthweight was 3.8 kg (50th centile), progressive weight gain led to a weight of 32 kg (more than 99th centile) at the age of 4 years. There was a history of hyperphagia with constant food seeking and distress when food was not provided. Fasting serum leptin concentration was appropriate for the degree of obesity. The mother was not obese and had a normal appetite. The father, aged 30 years, weighed 139 kg at a height of 185 cm. He was also of normal birth weight, but his weight began to deviate from predicted centiles at 6 months of age. The patient had no sibs and no further information concerning his parents was available.

Vaisse et al. (1998) described a 35-year-old woman with severe obesity that developed in infancy. Her birth weight was normal, but her weight was 45 kg with a height of 141 cm at age 10 years, and 80 kg with a height of 163 cm at age 20. Blood glucose and plasmid lipid levels were normal; serum leptin levels were consistent with her adiposity. She belonged to a large family of obese subjects: her mother, sister, niece, and a younger brother were also obese.

Dubern et al. (2001) studied 4 French families with severe obesity and heterozygous mutations in the MC4R gene. The authors reported reduced penetrance in 2 families: in 1 family, the proband's sister, who was also heterozygous for the mutation, had a BMI within the normal range for her age; and in another family, the proband's carrier mother was of normal weight and had no history of obesity. The authors also stated that they found no specific phenotype associated with MC4R mutations, and noted that in contrast to earlier reports, no excessive hunger or food-seeking behaviors were observed.

Farooqi et al. (2003) studied 17 families with severe obesity, including 11 with heterozygous mutations in MC4R and 6 with homozygous MC4R mutations. They observed a clinical phenotype associated with MC4R deficiency, including hyperphagia, severe obesity, increased lean body mass, and increased linear growth, as well as severe hyperinsulinemia that was disproportionate for the degree of obesity, compared to obese individuals without MC4R mutations. In addition, homozygotes were more severely affected and had a higher mean percentage of body fat than heterozygotes.

Greenfield et al. (2009) studied blood pressure and metabolic data in 46 MC4R-deficient overweight or obese adults from 32 families, previously identified in the Genetics of Obesity Study (Farooqi et al., 2003), as well as in 30 overweight or obese adults with normal MC4R sequence. The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24 vs 53%, p = 0.009), and the differences in blood pressure levels were not explained by changes in insulin levels. In addition, MC4R-deficient subjects had a lower increase in heart rate on waking (p = 0.007), a lower heart rate during euglycemic hyperinsulinemia (p less than 0.001), and lower 24-hour urinary norepinephrine excretion (p = 0.04) compared to controls. The authors concluded that effects of weight loss and obesity on blood pressure may involve alterations in central melanocortinergic signaling, through an insulin-independent mechanism mediated through changes in sympathetic neural activity.

Inheritance

The transmission pattern of early-onset severe obesity in the families reported by Yeo et al. (1998) and Vaisse et al. (1998) was consistent with autosomal dominant inheritance.

Mapping

In a genomewide association study of 318,237 SNPs for insulin resistance and related phenotypes in 2,684 Indian Asians and 11,955 individuals of Indian Asian or European ancestry, Chambers et al. (2008) found association between rs12970134, located near the MC4R gene, and waist circumference (p = 1.7 x 10(-9)). Homozygotes for the risk allele had an approximately 2 cm greater waist circumference compared to wildtype. The authors concluded that genetic variation near MC4R is associated with a risk of adiposity and insulin resistance.

Molecular Genetics

Obesity

Yeo et al. (1998) and Vaisse et al. (1998) described a severely obese child and adult, respectively, with heterozygous frameshift mutations in the MC4R gene (155541.0001 and 155541.0002).

Dubern et al. (2001) searched for mutations in the genes encoding the melanocortin-4 receptor, alpha-MSH (see 176830), and agouti-related protein (602311) in 63 severely obese children. Four dominantly inherited heterozygous missense MC4R mutations (155541.0005-155541.0008) were identified in 4 unrelated children and none of the control subjects. Expression of the obese phenotype was variable in mutation-positive family members. Dubern et al. (2001) concluded that MC4R mutations may be a nonnegligible cause of severe obesity in children with variable expression and penetrance.

In 29 (5.8%) of 500 probands with severe childhood obesity, Farooqi et al. (2003) identified heterozygous and homozygous mutations in the MC4R gene (155541.0010-155541.0019). Homozygotes were more severely affected than heterozygotes, and individuals with mutations retaining residual signaling capacity had a less severe phenotype.

In 24 (5.1%) of 469 severely obese white subjects (370 women and 99 men) and 1 (4%) of 25 normal-weight controls (15 women and 10 men), Branson et al. (2003) identified mutations in the MC4R gene. All mutation carriers reported binge eating, as compared with 14.2% of obese subjects without mutations and none 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. List and Habener (2003) commented on the possible importance of ethnic background in the frequency of mutations in MC4R in obesity. They also suggested that the findings of Branson et al. (2003) be interpreted with caution, as they differed from earlier findings of a binge-eating disorder prevalence of 5% among carriers of MC4R mutations (Sina et al., 1999).

Hebebrand et al. (2004) compared the eating behavior of 43 obese probands with functionally relevant MC4R mutations to wildtype controls. No significant differences in binge-eating episodes between carriers of the MC4R variants and wildtype controls were detected, and Hebebrand et al. (2004) concluded that binge-eating episodes are not a distinct feature of MC4R mutation carriers. This analysis was different from the study of Branson et al. (2003) because Hebebrand et al. (2004) studied only carriers of mutations that had been shown to be of functional relevance in vitro and did not include carriers of silent variants in the open reading frame, variants in UTRs, or the val103-to-ile (V103I) or ile251-to-leu (I251L) polymorphisms.

Calton et al. (2009) studied MC4R and MC3R (155540) variants detected in a total of 1,821 North American adults (889 severely obese and 932 lean controls) from 2 cohorts. The total prevalence of rare MC4R variants in the severely obese adults was 2.25% (95% CI, 1.44-3.47) compared with 0.64% (95% CI, 0.26-1.43) in the lean controls (p less than 0.005). After classification of functional consequence, the prevalence of MC4R mutations with functional alterations was significantly greater when compared with controls (p less than 0.005). Calton et al. (2009) concluded that mutations in MC4R are a significant cause of severe obesity in North American adults. They did not find an association between variants in the MC3R gene and severe obesity in this population.

Resistance to Obesity

In a transmission/disequilibrium test on 520 trios with obesity, Geller et al. (2004) unexpectedly observed a lower transmission rate of the MC4R V103I allele (155541.0024; p = 0.017). Metaanalysis of combined data from 7,713 individuals, primarily samples of European origin, in 2 large case-control studies and 12 published studies demonstrated a negative association of the 103I allele with obesity (odds ratio, 0.69; p = 0.03). Noting the apparent protective effect against obesity, the authors suggested that variation in the MC4R gene might entail both loss and gain of function.

Heid et al. (2005) analyzed data from 2 large population-based surveys from the Augsburg region of southern Germany, with a total of 7,937 participants. By linear regression, they found a significant decrease of 0.52 BMI units (p = 0.043) for heterozygous carriers of the MC4R V103I variant, which was observed in 3.7% of participants. Logistic regression analysis yielded a significantly negative association of the MC4R variant with above-average weight (odds ratio, 0.75; p = 0.017). Similar results were obtained in a comparison of obese (BMI > 30) to nonobese participants of either sex (odds ratio, 0.69; p = 0.026). The authors concluded that the V103I polymorphism could be regarded as contributing to polygenetically regulated body weight.

Lotta et al. (2019) analyzed 61 nonsynonymous variants in the MC4R gene in 452,300 participants of European ancestry in the UK Biobank database, using time-resolved assays to quantify cAMP production and beta-arrestin-2 (ARBB2; 107941) recruitment. The assays showed that 58 (95%) of the 61 missense variants had functional consequences: 47 (77%) resulted in loss of function and 9 (15%) in a significant gain of function, 2 (3%) had opposing effects on the 2 signaling pathways, and 3 (5%) were wildtype-like in both assays. Most of the variants affected both cAMP production and the recruitment of beta-arrestin to MC4R. Association studies revealed that loss-of-function variants were associated with higher BMI and higher odds of obesity, type 2 diabetes, and coronary artery disease, whereas gain-of-function variants were strongly associated with lower BMI and lower odds of obesity, severe obesity, and coronary artery disease, as well as lower diastolic blood pressure and lower resting heart rate. Random-effects metaregression demonstrated that beta-arrestin recruitment was a statistically significant predictor of the association of different MC4R variants with BMI, explaining 88% of the variance in those associations, whereas cAMP production was not.