'Complicated' best descriptor for red hair gene

National report - Findings from a decade's worth of research focusing on the melanocortin 1 receptor (MC1R) gene show that it is a complicated gene.

MC1R comes complete with pleiotropic effects and is associated with multiple variations that underlie a complex range of phenotypic diversity, according to Jonathan Rees, F.R.C.P., F.Med.Sci., professor of dermatology, University of Edinburgh, Scotland.

In 1995, Dr. Rees and collaborators at the University of Newcastle, including Tony Thody, Ph.D., and Ian Jackson, Ph.D., first identified MC1R as a gene associated with red hair, fair skin and tanning response. Subsequent studies showed that MC1R is also a genetic risk factor for melanoma and non-melanoma skin cancer.

MC1R influences hair and skin color because it regulates melanocyte synthesis of red/yellow pheomelanin and black/brown eumelanin.

In their original research, Dr. Rees and colleagues showed that MC1R gene sequence variants were present in more than 80 percent of persons with red hair and/or fair skin that tanned poorly compared with fewer than 20 percent of persons with brown or black hair and in less than 4 percent of individuals who tanned readily.

"It seems that MC1R is still the only gene that could be physically identified at the scene of the crime and usefully predict a particular phenotype - in this case hair color," Dr. Rees tells Dermatology Times.

Studies using colorimetric determination of hair color and high performance liquid chromatography (HPLC) to measure hair content of eumelanin and pheomelanin showed there was a significant correlation between MC1R genotype and the ratio of those melanin types. Similarly, the number of body sites affected by freckling was found to be greatest in homozygotes and intermediate in heterozygotes.

Vagaries of gene variance

Over 70 different sequence variants of MC1R have been identified so far in humans, although a handful appear to account for a large proportion of the variations seen in the population.

Of particular interest, in vitro cell transfection studies and investigations in transgenic mice indicate that specific variants have different physiological consequences in terms of determining the amount and type of pigment produced.

"For this single gene there are many different sequence variants that have quantitatively different effects, and it is not a simple case where the presence or absence of a mutation has consequences that are black or white, pardon the pun. Depending on the combination of the two alleles, the physiological signal can either be 100 percent, very low or, more likely, somewhere in between, such that a whole range of skin color, hair color and susceptibility to UV radiation can be produced," Dr. Rees says.

Consideration of MC1R as a candidate gene for melanoma susceptibility was based on its association with other risk factors for that skin cancer, i.e., red hair, fair skin and sun sensitivity. Studies evaluating associations between MC1R mutations and melanoma show that the risk of that skin cancer is highest among homozygotes. However, even heterozygotes without red hair have a two-to four-fold increased risk for developing skin cancers relative to wild-type individuals.

Complex, cause and effect debatable

There is debate about whether association of MC1R with skin cancer can solely be explained by the effects of MC1R on pigmentation, or, by contrast, is related to the effects of MC1R on DNA repair.

"There is a controversy in the literature about whether the elevated risk of cancer seen in those people with MC1R variants is due to MC1R influence on skin color alone or whether an effect of MC1R on UVR-induced DNA repair may also be relevant," Dr. Rees says.

Whether the development of variation in MC1R is purely due to chance or reflects natural selection favoring those with pale skin in geographic areas where there is little ultraviolet radiation available to synthesize vitamin D is also still unclear.

"A range of other genes have recently been identified that are also important in the pigmentary phenotype, and studies of these should resolve this issue in the near future," Dr. Rees says.