Melanocytes make two forms of melanin in the skin, hair, and eyes.
- Eumelanin is a dark pigment that protects against the harmful effects of ultraviolet radiation (UVR) from the sun.
- Phaeomelanin is a lighter pigment, which is associated with increased susceptibility to free radical damage from UVR [1,2].
Red hair, fair skin and freckles — the effects of phaeomelanin
What is the melanocortin 1 receptor gene?
The melanocortin 1 receptor (MC1R) gene encodes the receptor of melanocortin-stimulating hormone (also referred to as melanocyte-stimulating hormone or MSH), which is found on the surface of melanocytes.
- Binding of MSH to MC1R promotes adenylate cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP) levels .
- This switches pigment production from phaeomelanin to eumelanin.
MC1R is maps to chromosome 16q24.3, meaning it is located on the long arm of chromosome 16, in position 24.3 near the telomere (the protective cap at the end of the chromosome that shortens with every replication) .
What are the variants of MC1R gene?
The MC1R gene is highly polymorphic in Caucasian populations, with more than 80 variants being described in the population [1–5]. While the exact number of people carrying the MC1R gene variants is difficult to determine globally, population-based studies have estimated that 1–2% of the population carries a variant allele for this gene. This number is very variable depending on the region and population.
In populations with North European ancestry:
- Four variants of the MC1R gene (V60L, V92M, R151C and R160W) occur, at a frequency of 5%
- Five variants of the MC1R gene (D84E, R142H, I155T, R163Q and D294H) occur in 1–5% of the population
- Other alleles occur at a frequency of less than 1% .
What are MC1R-related phenotypes?
A phenotype refers to the observable features related to a gene; in the case of the MC1R gene a related phenotype is hair colour.
Hair colour is an autosomal recessive trait expressed by the MC1R gene.
- Most individuals with pure red hair colour (RHC) are homozygous for two variant MC1R alleles.
- The high penetrance genes (namely, R151C, R160W, D294H and D84E) are denoted as 'R' and almost always result in red hair colour when homozygous (RR) [5–7].
- People with strawberry blonde or auburn hair colour are heterozygous, carrying only one hypomorphic variant allele (Rr).
Not all MC1R variants are associated with red hair.
- The V60L, R163Q and V92M variants, denoted as “r”, do not produce red hair when in combination with the highly penetrant alleles, due to either a slight functional impairment or normal coupling of cAMP pathway.
- V60L is common in the general non-RHC population (15%≤), including Asian populations and Caucasians with darker skin, and is considered a silent mutation .
What are the clinical features of MC1R variants?
People carrying a homozygous (RR) or compound (Rr) heterozygous R allele will often have at least one of the following characteristic features:
- A degree of red, auburn, or strawberry blonde hair (scalp and beard)
- Fair skin
- Light eye colour
- Sun sensitivity (poor tanning response and solar lentigines)
- Family members with similar characteristics.
What are the complications of MC1R variants?
MC1R germline mutations have been shown to increase the risk of cutaneous melanoma. MC1R phenotypic traits make an individual more susceptible to ultraviolet (UV) damage and melanoma may occur without excessive UV exposure. In patients with MC1R gene variants, melanoma occurs more frequently and at an earlier age at onset than in the general population.
Other germline mutations that increase the risk of melanoma include cyclin-dependent kinase inhibitor 2A (CDKN2A), and cyclin-dependent kinase 4 (CDK4) .
The risk of melanoma due to MC1R mutation is moderate compared to that occurring with CDKN2A and CDK4 mutations. MC1R variants may modify CDKN2A penetrance, increasing the incidence and decreasing the age at onset of melanoma by up to 21 years, when compared to individuals with CDK2NA mutations alone .
Some studies have suggested individuals with at least one MC1R variant allele had a 5–15-fold increase in susceptibility to v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutant melanomas . This finding needs further investigation, as other studies have not found the same association.
How are MC1R variants diagnosed?
A thorough genetic pedigree can indicate whether there is a MC1R gene variant that runs in the family and its inheritance pattern. Genetic testing can be indicated if there is a strong family history of melanoma in individual with red hair and other phenotypic traits.
However, genetic testing for MC1R variants is most often undertaken for research purposes. The entire coding region is assessed through a bi-directional Sanger sequence analysis.
What can I do if I have a MC1R variant?
People likely to have MC1R variants, who have red or blonde hair, light eye colouring and freckles, should be aware that they are at increased risk of melanoma, as well as other forms of skin cancer.
Sun-safe behaviour includes wearing sun-protective clothing, applying sunscreen at regular intervals when outdoors, and avoiding intense or frequent sunburn.
People carrying the MC1R variant genes should be advised to undertake regular self-skin examination from early adult life and to undertake skin checks by a trained health professional. Watch out for pigmented and non-pigmented skin lesions with the following characteristics:
- The 'ugly duckling' — the lesion looks different from their other lesions
- A lesion that is enlarging or changing in colour, shape and structure
- A lesion with 'ABCD' features:
- Border irregularity
- Colour variation
- Diameter > 6 mm (large size).