Melanocortin 3 receptor gene and melanocortin 4 receptor gene mutations: the Asian Perspective


  • Yung Seng Lee

    Corresponding author
    1. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
    2. University Children’s Medical Institute, National Univesity Hospital, Singapore
    3. Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore
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*Correspondence to:
Associate Professor Lee Yung Seng,
Department of Paediatrics,
Yong Loo Lin School of Medicine,
NUHS Tower Block, Level 12,
1E Kent Ridge Road,
Singapore 119228, Singapore


Melanocortin 4 receptor (MC4R) deficiency resulting from disruption of one or both MC4R alleles represents the commonest monogenic form of human obesity to date. Human MC4R deficiency was reported to affect 4 and 5.8% of severely obese French and British populations respectively. However, studies elsewhere reported low incidence of MC4R mutations in their obese populations. The significance of MC4R mutations in Asian obese populations has not been adequately examined, though small studies in Japan, China, and Singapore reported few or no pathogenic mutations, suggesting a low prevalence in this part of the world. There were also few common mutations described across populations, suggesting a relative lack of founder effect. The pathogenic role of melanocortin 3 receptor gene (MC3R) mutations in human obesity is not as well described and accepted as MC4R mutations, though it is gradually gaining ground. Two common single nucleotide polymorphisms Thr6Lys and Val81Ile within the coding region were associated with higher body fat and leptin levels in obese children, supported by impaired signaling activity in vitro. There were also reports of missense mutations enriched in obese populations. While MC3R mutations are unlikely to result in an autosomal dominant form of monogenic obesity given the lack of strong co-segregation in family studies, the studies so far provided evidence that MC3R can be one of the genes which contributes to increased adiposity, and exert an effect on the human phenotype.