reported a prevalence of MC4R LoF mutations of 1.7% in obese European adults and that obesity in carriers of the same mutation differed across generations within the same families, providing evidence for gene-environment interaction 19. For example, in a population-based cohort from Germany, Hinney et al., using a mutational scanning technique, reported a prevalence of LoF mutations in MC4R of ~0.1% 15. While early reports based on clinically ascertained cohorts suggested a high penetrance of early-onset obesity, subsequent studies of less highly selected patients demonstrated that the carriage of LoF mutations was not always associated with obesity 15, 19. Many MC4R LoF mutations have been described in obese individuals and families 14– 16 and the severity of disruption of MC4R signalling resulting from such mutations has been reported to correlate with adiposity and degree of hyperphagia 17, 18. Subsequent studies reported more severe obesity in homozygotes, suggesting a semi-dominant form of inheritance 13. However, in the case of mutations in the MC4R gene, severe early-onset obesity has been reported in multiple affected members of several families who only carried heterozygote LoF mutations 4, 12.
Severe early-onset human obesity associated with mutations in genes encoding leptin or the leptin receptor are very rare and observed only in individuals homozygous for loss of function (LoF) mutations in those genes 3, 5. Leptin acts on hypothalamic neurons to promote the release of melanocortins and suppress the secretion of the melanocortin antagonist, agouti-related peptide (AGRP) 9, 11. The binding of its natural agonists, the pro-opiomelanocortin-derived melanocortin peptides, alpha and beta melanocyte-stimulating hormone (MSH), results in the suppression of food intake and the activation of a subset of autonomic neurons of the sympathetic nervous system 8– 10. Specifically, the melanocortin 4 receptor (MC4R) is a G-protein coupled, seven-transmembrane receptor expressed widely in the central nervous system 6, 7. The critical role of the leptin-melanocortin system in the long-term sensing of body fat stores was first established in the 1990s, with defects in this system resulting in obesity in rodents and humans 1– 5. Mutations disrupting the leptin-melanocortin system have frequently been reported in severe, early-onset human obesity but the prevalence and extent of phenotypic impact of such mutations are unclear. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and non-carriers of LoF mutations were 17.76kg (95% CI: 9.41, 26.10), 4.84kg/m 2 (95% CI: 2.19, 7.49) and 14.78kg (95% CI: 8.56, 20.99), respectively. The frequency of heterozygous loss of function (LoF) mutations in MC4R was ~1/337 (0.30%), considerably higher than previous estimates. We examined the MC4R coding sequence in 5724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterised all non-synonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. Mutations in the melanocortin 4 receptor gene ( MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development.
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