Melanocortin 1 Receptor Variants: Functional Role and Pigmentary Associations

The significance of human cutaneous pigmentation lies in its protective role against sun-induced DNA damage and photocarcinogenesis. Fair skin and red hair are characterized by a low eumelanin to pheomelanin ratio, and have been associated with increased risk of skin cancer. Cutaneous pigmentation is a complex genetic trait, with more than 120 genes involved in its regulation, among which the melanocortin 1 receptor gene (MC1R) plays a key role. Although a large number of single nucleotide polymorphisms (SNPs) have been identified in pigmentation genes, very few SNPs have been examined in relation to human pigmentary phenotypes and skin cancer risk. Recent GWAS have identified new candidate determinants of pigmentation traits, but MC1R remains the best characterized genetic determinant of human skin and hair pigmentation as well as the more firmly validated low-penetrance skin cancer susceptibility gene. In this review, we will address how the melanocortin system regulates pigmentation, the effect of MC1R variants on the physiologic function of the MC1 receptor, and how specific MC1R variants are associated with distinct human pigmentation phenotypes.