The Melanocortin 1 Receptor (MC1R): More Than Just Red Hair

Abstract

The melanocortin 1 receptor, a seven pass transmembrane G ing loss-of-function mutations. Activating mutations of the protein coupled receptor, is a key control point in melanogen-MC1R in man have not been described. The MC1R is particesis. Loss-of-function mutations at the MC1R are associated ularly informative and a tractable gene for studies of human evolution and migration. In particular, study of the MC1R with a switch from eumelanin to phaeomelanin production, resulting in a red or yellow coat colour. Activating mutations, may provide insights into the lightening of skin colour observed in most European populations. The world wide pattern of in animals at least, lead to enhanced eumelanin synthesis. In MC1R diversity is compatible with functional constraint operman, a number of loss-of-function mutations in the MC1R have been described. The majority of red-heads (red-haired ating in Africa, whereas the greater allelic diversity seen in persons) are compound heterozygotes or homozygotes for up to non-African populations is consistent with neutral predictions five frequent loss-of-function mutations. A minority of redrather than selection. Whether this conclusion is as a result of heads are, however, only heterozygote. The MC1R is, thereweakness in the statistical testing procedures applied, or whether it will be seen in other pigment genes will be of great fore, a major determinant of sun sensitivity and a genetic risk interest for studies of human skin colour evolution. factor for melanoma and non-melanoma skin cancer. Recent work suggests that the MC1R also shows a clear heterozygote Key words: MC1R, Loss-of-function mutation, Red-heads, effect on skin type, with up to 30% of the population harbourRed hair, Skin type, Skin colour other genetically complex states. Most genes involved in human pigmentation, including the MC1R, have been identified on the back of the resource and tractable experimental system provided by the marriage of the mouse mutant resource and modern molecular genetics (4 -7). So far, however, the MC1R is the only gene that is known to explain physiological variation in human pigmentation (rather than just rare Mendelian phenotypes such as albinism) (8, 9). Much potential interest in the MC1R therefore relates to the methodological problems inherent in relating sequence data to physiological state with a simple Mendelian framework. Work on the MC1R is therefore facing a combination of methodological problems that have not arisen with other pigment genes, including the presence of a large number of alleles; the relation between follicular and interfollicular pigmentation; and perhaps the most significant of all, how to assay human pigmentation and the cutaneous response to ultraviolet radiation in such a way that it is amenable to a

Incidence trends and familial risks in invasive and in situ cutaneous melanoma by sun‐exposed body sites

“…Some suggested low-penetrance genes for melanoma include polymorphic variants of melanocortin-1 receptor and many DNA repair genes. [32][33][34][35][36] On the other hand, the identified mutations in the CDKN2A gene show high penetrance. 39 An interesting aspect of the international penetrance study on CDKN2A was the correlation to the background risk: penetrance was higher in high-risk areas, Australia and the United States, compared to Europe.…”

“…11,20 -26 Genetic causes are mediated by high-risk genes, such as CDKN2A (p16) and CDK4, 21,22,[27][28][29] their common polymorphic forms 30,31 or low-penetrance variants of genes, such as melanocortin-1 receptor, and many DNA repair genes. [32][33][34][35][36] However, direct measurements of DNA repair rates for UV damage have shown no difference between melanoma patients and controls. 37,38 Recent data suggest that the penetrance of the CDKN2A gene depends on the background prevalence of melanoma, being highest in the high-incidence countries of Australia and the United States.…”

Fisiopatologia do melasma

“…Foi conhecido, por muitos anos, o envolvimento dos dois loci na regulação qualitativa (eumelanina e feomelanina) e quantitativa da pigmentação de mamíferos, sendo a ASP produzida nos folí-culos e agindo nos melanócitos foliculares, pela inibição da síntese de eumelanina. 17,38,39 Previamente à clonagem, dois receptores de melanocortina, receptor de MSH e ACTH, foram descobertos por estudos farmacológicos e fisiológicos clássicos.…”

“…17,38,39 O MC1-R foi o primeiro receptor de α-MSH a ser clonado e foi isolado de uma linhagem celular de melanoma. 34 O gene do MC1-R humano está localizado no cromossomo 16q24.3 e mostra uma estrutura de leitura de 951 pares de base que codificam uma proteína de 317 aminoácidos.…”

“…Se o MC1-R está envolvido em outras vias sinalizadoras, ainda permanece desconhecido, mas a ativação do MC1-R influencia as quantidades relativas de feomelanina e eumelanina produzidas, sendo sua perda de atividade, associada a cabelos vermelhos ou amarelos. 20,34,38,39,[48][49][50][51][52] Variantes do MC1-R têm sido associadas com a herança de cabelo vermelho, na qual mais pigmento amarelo-avermelhado de feomelanina é produzido e apresentam capacidade de bronzeamento muito pequena. Variantes R160W, R151C, D294H, R142H, 86insA e 537insC de MC1-R são os principais determinantes do fenótipo de cabelos vermelhos e pele clara.…”