The Melanocortin-1 receptor (Mc1r) is one of the key proteins in hair colour production. When stimulated by α-Melanocyte stimulating hormone (α-MSH), it will lead to the production of dark Eumelanin. The signalling can be interrupted by Agouti signalling protein (Asip) which anatagonizes α-MSH binding and leads to the production of lighter Phaeomelanin.
Mutations of the Mc1rgene can either create a receptor that constantly signals, even when not stimulated, or can lower the receptors activity. Alleles for constantly active Mc1r are inherited dominantly and result in a black coat colour, while alleles for non-funtional Mc1r are recessive and result in a light coat colour. Red hair colour in humans is usually due to a mutated Mc1r gene.
When the MC1R is stimulated with α-MSH, cyclic-AMP levels increase which leads to an increase in protein kinase A. The increase in protein kinase A leads to an increase in the transcription of microphthalmia transcription factor.
Therefore, individuals with loss of function of MC1R may be at increased risk for skin cancer due to lack of eumelanin, lack of differentiation of melanocytes and loss of the inherent defense mechanisms of melanocytes and keratinocytes.
In addition to MC1R loss of function alleles conferring risk for melanoma, these alleles have also been shown to increase the risk for basal cell and squamous cell carcinomas with an odds ratio of 3.15 (95% CI) specifically for the Arg151Cys, Arg160Trp, and Asp294His alleles [15].
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