The Golden Melanocyte Award

6th Meeting of the ESPCR (Lausanne, Switzerland) Oct. 1995

Melanin pigmentation plays an essential role in protecting the skin from the damaging effects of ultraviolet radiation (UVR)

P. Valverde, E. Healy, I. Jackson*, J.L. Rees, A.J. Thody

Dept of Dermatology, University of Newcastle upon Tyne,

*MRC human Genetics Unit, Western General Hosp. Edinburg, UK


In mammals, there are at least two types of melanin, the red/yellow phaeomelanin and the brown/black eumelanin, both of which are present in human skin (1). Of these two types of melanin, eumelanin has the more significant role in protection against UVR whereas phaeomelanin, because of its greater potential to produce free radicals in response to UVR (2), which are capable of inflicting cell injury, may actually contribute to UV-induced skin damage. Thus, the susceptibility to photocarcinogenesis and possibly the tanning ability may depend not simply on the amount of melanin in the skin but also upon the type of melanin produced in the melanocytes.

In mice and other mammals the relative proportions of phaeomelanin and eumelanin are regulated by melanocyte-stimulating hormone (MSH), which acts via its receptor (MC1R), on melanocytes, to increase the synthesis of eumelanin (3,4) and the product of the agouti locus which antagonises this action (5). In mice, mutations at either the MC1R or agouti genes affect the pattern of melanin synthesis resulting in coat colour changes (6,7).

The purpose of the present study was to determine whether MC1R variants occur in humans as in other mammals and whether they are related to their pigmentation phenotype.

Because of the polygenic nature of human pigmentation, 60 British or Irish Caucasians were selected from individuals showing extremes of hair colour, that is either red or black. Genomic DNA was extracted from blood or mouthwash samples and the coding region of the MC1R gene analysed by nested PCR followed by direct cycle sequencing. This methodology enabled us to determine that the 30 dark-haired individuals that we examined had no variations respect to the sequence previously published for the coding region of the MC1R gene (8). In contrast, 70 % of the red-haired population had at least one substitution in this gene. In total, 9 different heterozygous variations were identified (A64S, F76Y, D84E, V92M, T95M, V97I, A103V, L106Q, D294H). 8 of them were located in a region of 42 aminoacids between the first cytoplasmic loop and the first extracellular loop spanning the second transmembrane domain. This location was very similar to that previously found for the dominant mutations of the MC1R gene in mice (9). On the other hand, the substitution at codon 294 was located in the seventh transmembrane domain. The D294H change was the most common (53 %) followed by the variation at codon 92 (27 %). However, from the functional point of view, the variations at codons 84, 106 and 294 may be the most important, since these positions are highly conserved in the melanocortin receptor family (8,10,11).

Since we only found variations in the MC1R gene sequence from the red-haired individuals as opposed to those from the dark-haired ones, we examined whether these substitutions were related to a specific shade of red hair. To do this, we subclassified the red-haired population according to their shades of red hair as light-red, deep-red and auburn or brownish-red. The variation at codon 294 was found in all three groups, the substitution at codon 92 occurred in light-red and deep-red haired individuals, while all the other changes were seen either in light-red or deep-red haired ones. Moreover, 8 of these individuals with light-red or deep-red hair had a combination of two, three or even four substitutions in their MC1R gene (D294H & T95M; D294H & V97I; V92M & L106Q; two with D294H & V92M; D294H, V92M & A64S; D294H, V92M & D84E; D294H, V92M, A64S & D84E). The cloning of their PCR products and the subsequent sequencing of several clones showed that only one had the variations at the same allele of the gene (D294H & V97I) while the remaining 7 were compound heterozygous. These results pointed to a complex relationship between the red hair phenotype and the MC1R genotype. On the other hand, these data did not discount the possibility that the MC1R variants were present in individuals with intermediate hair phenotype between the extremes red and black. We therefore analysed a new group of 75 volunteers with different hair colours ranging from one extreme to the other. The results obtained from these 75 individuals were pooled whith those the 60 previously examined. 82 % of light-red/deep-red haired persons had changes in one or both alleles, compared with 22 % auburns, 33 % of fair or blondes and less than 20 % of the brown or blacks. The ocurrence of some subtitutions (only at codons 92, 103 or 294) in some individuals with intermediate hair phenotype and even with black hair indicated that the MC1R variants were not exclusively associated with red hair. It was possible however that they were related to the poor tanning ability which characterises the red-haired population. To examine this possibility, we classified the individuals' skin type by using the Fitzpatrick classification and found the highest frequency of any MC1R variation in individuals with skin type I (76.5 %), followed by those with skin type II (46.5 %). No individuals with skin type IV and only 5 % with skin type III had changes. In addition, only persons with skin type I or II, who also had light-red or deep-red hair had more than one substitution or substitutions at both alleles of the gene.

Our findings suggest that in humans as in other mammals, MC1R may be a control point in the regulation of pigmentation phenotype, and more importantly, that variations in this protein are associated with a poor tanning in humans. Functional and mapping studies are now in progress to determine whether MC1R may be used in the future as a marker for the study of human population genetics and to clarify the wide variations in pigmentation and the susceptibility to skin cancer in humans.


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