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Jonathan L. Rees - One of the best experts on this subject based on the ideXlab platform.

  • The Human Melanocortin-1 Receptor
    The Melanocortin Receptors, 2020
    Co-Authors: Eugene Healy, Mark A. Birch-machin, Jonathan L. Rees
    Abstract:

    One of the more obvious features that distinguishes one human from another are the pigmentatory characteristics (including skin type, hair and eye color) of the individual. Although it had been suspected (as a result of investigations into murine coat color) that several genes were likely to be involved in human pigmentation, and, although it had been known for some time that proopioMelanocortin (POMC) peptides such as alpha-melanocyte stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH) can alter cutaneous pigmentation, it has only been during the past 10 years that molecular biologic/ genetic approaches have offered some insight into the complexities of human pigmentation (1–3). The detection of mutations within the genes responsible for type I and type II oculocutaneous albinism and piebaldism provided evidence for genotypic/phenotypic relationships in a subset of individuals with pigmentatory disorders, but did little to explain the wide variability in the pigmentatory characteristics of the vast majority of individuals (4–6).However, a basis for understanding “normal” human pigmentation became possible with the initial cloning of the human Melanocortin 1 Receptor (MC1R) gene by three separate groups who isolated this gene on the basis of its similarity to other G protein-coupled Receptors (7,8) , and the subsequent identification of variant alleles within the murine homolog of this gene (mc1r) which could differentially activate adenylyl cyclase and which were associated with various coat colors in mice (9).

  • Genetic studies of the human Melanocortin-1 Receptor.
    Annals of the New York Academy of Sciences, 2006
    Co-Authors: Jonathan L. Rees, Niamh Flanagan, Mark A. Birch-machin, Eugene Healy, Siôn R. Phillips, Carole Todd
    Abstract:

    : Genetic approaches have suggested a critical role for the Melanocortin-1 Receptor in the control of pigmentation. We showed that this gene is unusually polymorphic in European populations and that, of the many variants, three in particular appear to be associated with red hair or fair skin. Family studies suggest these are inherited as an autosomal recessive trait (or at least approximate to this in many families). To date all individuals with two of these three changes (homozygote or compound heterozygote) have red hair. Early functional studies are in keeping with defective signalling through MC1R. An interested and perhaps unexpected question relates to the evolutionary factors that have given rise to such variants. Two models can be proposed, that are based on multiple alleles with minor changes in function or genetic hitch-hicking.

  • the relation between Melanocortin 1 Receptor mc1r variation and the generation of phenotypic diversity in the cutaneous response to ultraviolet radiation
    Peptides, 2005
    Co-Authors: Terence Hawkin Wong, Jonathan L. Rees
    Abstract:

    The Melanocortin 1 Receptor (MC1R) is known to play an important role in determining physiological variation in human pigmentation, and consequently human susceptibility to ultraviolet radiation. A reason for wider interest is that the considerable phenotypic diversity has been in part generated by the effects of gene dosage, and the presence of a large number of mutations at this G-protein coupled Receptor that are not functionally equivalent. Thus, a range of mutations at a single Receptor locus can lead to a complex range of graded phenotypes.

  • quantitative measures of the effect of the Melanocortin 1 Receptor on human pigmentary status
    Journal of Investigative Dermatology, 2004
    Co-Authors: Lisa Naysmith, Niamh Flanagan, Jonathan L. Rees, Tom Ha, Karen Waterston, Yvonne Bisset, Kazumasa Wakamatsu
    Abstract:

    Variation in human hair and skin color is the most striking visible aspect of human genetic variation. The only gene known to exert an effect on pigmentary within the normal population is the Melanocortin-1 Receptor (MC1R). Previous studies have used a Mendelian framework to relate MC1R genotype to phenotype, by measuring pigmentary status using categorical scales. Such approaches are inadequate. We report results using direct measures of hair color using objective colorimetric dimensions and HPLC determined hair melanins. We have linked MC1R genotype with chemical measures of melanin quantity and type and objective phenotype measures of color. MC1R genotype was predictive of hair melanin expressed as the ratio of the log e of eumelanin to pheomelanin ratio, with a dosage effect evident: MC1R homozygote mean, 1.46; heterozygote, 4.44; and wild type, 5.81 (p

  • Time course of ultraviolet B-induced erythema in people with red hair harbouring homozygous Melanocortin 1 Receptor mutations.
    Experimental Dermatology, 2003
    Co-Authors: Thomas Ha, Yvonne Bisset, Karen Waterston, Jonathan L. Rees
    Abstract:

    :  It has previously been reported that the time course of erythema may be delayed in those with sun-sensitive skin types and those with skin cancer. One molecular explanation for this putative phenotype would be that it is caused by mutations of the Melanocortin 1 Receptor (MC1R). In the present study of 20 persons, 10 of whom were MC1R homozygous, we measured erythema over a 21-day period in response to a range of ultraviolet B doses using methods that improved on previous studies. We could detect no consistent differences in ultraviolet radiation-induced erythema between the groups studied. The pharmacological mechanisms underpinning such prolonged inflammatory responses merit further investigation.

E Healy - One of the best experts on this subject based on the ideXlab platform.

  • variants of the Melanocortin 1 Receptor do they matter clinically
    Experimental Dermatology, 2015
    Co-Authors: E Healy, Ciara Haddadeen
    Abstract:

    The Melanocortin 1 Receptor (MC1R) gene encodes for a seven-pass transmembrane Receptor primarily expressed on melanocytes and melanoma cells. Single nucleotide polymorphisms (SNPs, also termed variants) in MC1R frequently cause red hair, fair skin and are associated with melanoma and keratinocyte-derived skin cancer development. Activation of wild-type (WT) MC1R in skin assists cutaneous photoprotection whereas reduced MC1R signalling, seen with MC1R variants, impairs ultraviolet radiation (UVR)-protective responses. As ancestral humans migrated out of Africa, the evolutionary advantage of MC1R variants may have related to improved cutaneous vitamin D synthesis and higher birthweight reported with certain MC1R variants. Reduced photoprotection secondary to MC1R dysfunction involves pigmentary and non-pigmentary mechanisms (reduced DNA repair, effects on cell proliferation and possibly immunological parameters), leading to clonal expansion of mutated cells within skin and subsequent carcinogenesis. Recent investigations suggest an association between MC1R genotype and vitiligo, with preliminary evidence that a MC1R agonist, [Nle4-D-Phe7]-alpha-MSH, in combination with UVB, assists repigmentation. Future development of compounds to correct defective MC1R responses secondary to MC1R variants could result in photoprotective benefits for fair-skinned individuals and reduce their skin cancer risk.

  • pleiotropic effects of the Melanocortin 1 Receptor mc1r gene on human pigmentation
    Human Molecular Genetics, 2000
    Co-Authors: Niamh Flanagan, Carole Todd, Ian J Jackson, E Healy, Mark A Birchmachin, Sion Philips, Jonathan L. Rees
    Abstract:

    Variants of the Melanocortin 1 Receptor (MC1R) gene are common in individuals with red hair and fair skin, but the relative contribution to these pigmentary traits in heterozygotes, homozygotes and compound heterozygotes for variants at this locus from the multiple alleles present in Caucasian populations is unclear. We have investigated 174 individuals from 11 large kindreds with a preponderance of red hair and an additional 99 unrelated redheads, for MC1R variants and have confirmed that red hair is usually inherited as a recessive characteristic with the R151C, R160W, D294H, R142H, 86insA and 537insC alleles at this locus. The V60L variant, which is common in the population may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrate that heterozygotes for two alleles, R151C and 537insC, have a significantly elevated risk of red hair. The shade of red hair frequently differs in heterozygotes from that in homozygotes/compound heterozygotes and there is also evidence for a heterozygote effect on beard hair colour, skin type and freckling. The data provide evidence for a dosage effect of MC1R variants on hair as well as skin colour.

  • Melanocortin 1 Receptor gene and sun sensitivity in individuals without red hair
    The Lancet, 2000
    Co-Authors: Carole Todd, Ian J Jackson, E Healy, Niamh Flannagan, J N S Matthews, Mark A Birchmachin, Jonathan L. Rees
    Abstract:

    Susceptibility to sunburn, photoageing, and skin cancer is inversely related to an individual's ability to tan after sun exposure. We examined variants in the Melanocortin-1-Receptor (MC1R) gene in individuals from Ireland and the UK. We found evidence of an association between the degree of tanning after repeated sun exposure, and the number of variant alleles present. Heterozygotes were intermediate between wild-type individuals and those with two variant alleles. We suggest that MC1R gene status therefore determines sun sensitivity in people without red hair.

David J Hunter - One of the best experts on this subject based on the ideXlab platform.

  • Melanocortin 1 Receptor variants and skin cancer risk
    International Journal of Cancer, 2006
    Co-Authors: Peter Kraft, Graham A Colditz, Jason Y Y Wong, David J Hunter
    Abstract:

    Melanocortin 1 Receptor (MC1R) gene variants are associated with red hair and fair skin color. We assessed the associations of common MC1R genotypes with the risks of 3 types of skin cancer simultaneously in a nested case–control study within the Nurses' Health Study (219 melanoma, 286 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 873 controls). We found that the 151Cys, 160Trp and 294His variants were significantly associated with red hair, fair skin color and childhood tanning tendency. The MC1R variants, especially the 151Cys variant, were associated with increased risks of the 3 types of skin cancer, after controlling for hair color, skin color and other skin cancer risk factors. Carriers of the 151Cys variant had an OR of 1.65 (95% CI, 1.04–2.59) for melanoma, 1.67 (1.12–2.49) for SCC and 1.56 (1.03–2.34) for BCC. Women with medium or olive skin color carrying 1 nonred hair color allele and 1 red hair color allele had the highest risk of melanoma. A similar interaction pattern was observed for red hair and carrying at least 1 red hair color allele on melanoma risk. We also observed that the 151Cys variant contributed additional melanoma risk amongred-haired women. The information on MC1R status modestly improved the risk prediction; the increase was significant for melanoma and BCC (p, 0.004 and 0.05, respectively). These findings indicated that the effects of the MC1R variants on skin cancer risk were independent from self-reported phenotypic pigmentation. © 2006 Wiley-Liss, Inc.

Kazumasa Wakamatsu - One of the best experts on this subject based on the ideXlab platform.

  • Redness Variation in the Eurasian Scops-Owl Otus scops is Due to Pheomelanin But is Not Associated with Variation in the Melanocortin-1 Receptor Gene (MC1R)
    Ardeola, 2019
    Co-Authors: Jesús M. Avilés, Kazumasa Wakamatsu, Ángel Cruz-miralles, Anne-lyse Ducrest, Céline Simon, Alexandre Roulin, Deseada Parejo
    Abstract:

    Melanin-based colorations in birds constitute a paradigm for the study of the molecular basis of phenotypic variation. Variation in the Melanocortin-1 Receptor (MCR1) gene, a key regulator of melanin synthesis in feather melanocytes, can lead to changes in the production of melanin and hence in feather colour. Here we investigate the proximate mechanisms behind colour plumage polymorphism in the Eurasian Scops-owl Otus scops, a species showing pronounced variation in the degree of redness. Although eumelanin pigment was three times more abundant than pheomelanin pigments, the degree of plumage redness was more strongly associated with the amount of pheomelanin than eumelanin pigments. We detected only one synonymous substitution and one non-synonymous substitution in MC1R which were, however, not associated with variation in plumage coloration. Redness variation in Eurasian Scops-Owls is primarily due to variation in pheomelanin, and to genes or regulatory elements other than MCR1. —Aviles, J.M., Cruz-Miralles, A., Ducrest, A.-L., Simon, C., Roulin, A., Wakamatsu, K. & Parejo, D. (2020). Redness variation in the Eurasian Scops-owl Otus scops is due to pheomelanin but is not associated with variation in the Melanocortin-1 Receptor gene (mc1r). Ardeola, 67: 3-13.

  • Melanocortin 1 Receptor genotype an important determinant of the damage response of melanocytes to ultraviolet radiation
    The FASEB Journal, 2010
    Co-Authors: Ana Luisa Kadekaro, Sancy A Leachman, Renny Kavanagh, Viki B Swope, Pamela B Cassidy, Dorothy M Supp, Maureen A Sartor, Sandy Schwemberger, George F Babcock, Kazumasa Wakamatsu
    Abstract:

    The Melanocortin 1 Receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between Melanocortin 1 Receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different Melanocortin 1 Receptor variants to α-Melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α-Melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the Receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on Receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional Receptor to α-Melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α-Melanocortin. Our findings highlight the molecular mechanisms by which the Melanocortin 1 Receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.—Kadekaro, A. L., Leachman, S., Kavanagh, R. J., Swope, V., Cassidy, P., Supp, D., Sartor, M., Schwemberger, S., Babcock, G., Wakamatsu, K., Ito, S., Koshoffer, A., Boissy, R. E., Manga, P., Sturm, R. A., Abdel-Malek, Z. A. Melanocortin 1 Receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation.

  • quantitative measures of the effect of the Melanocortin 1 Receptor on human pigmentary status
    Journal of Investigative Dermatology, 2004
    Co-Authors: Lisa Naysmith, Niamh Flanagan, Jonathan L. Rees, Tom Ha, Karen Waterston, Yvonne Bisset, Kazumasa Wakamatsu
    Abstract:

    Variation in human hair and skin color is the most striking visible aspect of human genetic variation. The only gene known to exert an effect on pigmentary within the normal population is the Melanocortin-1 Receptor (MC1R). Previous studies have used a Mendelian framework to relate MC1R genotype to phenotype, by measuring pigmentary status using categorical scales. Such approaches are inadequate. We report results using direct measures of hair color using objective colorimetric dimensions and HPLC determined hair melanins. We have linked MC1R genotype with chemical measures of melanin quantity and type and objective phenotype measures of color. MC1R genotype was predictive of hair melanin expressed as the ratio of the log e of eumelanin to pheomelanin ratio, with a dosage effect evident: MC1R homozygote mean, 1.46; heterozygote, 4.44; and wild type, 5.81 (p

Ryosuke Kimura - One of the best experts on this subject based on the ideXlab platform.

  • Association of Melanocortin 1 Receptor gene (MC1R) polymorphisms with skin reflectance and freckles in Japanese
    Journal of Human Genetics, 2012
    Co-Authors: Kyoko Yamaguchi, Chiaki Watanabe, Akira Kawaguchi, Takehiro Sato, Izumi Naka, Misaki Shindo, Keiichi Moromizato, Kenichi Aoki, Hajime Ishida, Ryosuke Kimura
    Abstract:

    Most studies on the genetic basis of human skin pigmentation have focused on people of European ancestry and only a few studies have focused on Asian populations. We investigated the association of skin reflectance and freckling with genetic variants of Melanocortin 1 Receptor ( MC1R ) gene in Japanese. DNA samples were obtained from a total of 653 Japanese individuals (ages 19–40 years) residing in Okinawa; skin reflectance was measured using a spectrophotometer and freckling status was determined for each individual. Lightness index ( L* ) and freckling status were not correlated with age, body mass index or ancestry (Ryukyuan or Main Islanders of Japan). Among the 10 nonsynonymous variants that were identified by direct sequencing of the coding region of MC1R , two variants—R163Q and V92M—with the derived allele frequencies of 78.6 and 5.5%, respectively, were most common. Multiple regression analysis showed that the 163Q allele and the presence of nonsynonymous rare variants (allele frequencies

  • association of Melanocortin 1 Receptor gene mc1r polymorphisms with skin reflectance and freckles in japanese
    Journal of Human Genetics, 2012
    Co-Authors: Kyoko Yamaguchi, Chiaki Watanabe, Akira Kawaguchi, Takehiro Sato, Izumi Naka, Misaki Shindo, Keiichi Moromizato, Kenichi Aoki, Hajime Ishida, Ryosuke Kimura
    Abstract:

    Association of Melanocortin 1 Receptor gene ( MC1R ) polymorphisms with skin reflectance and freckles in Japanese