Variants of the melanocyte–stimulating hormone receptor gene are associated with red hair and fair skin in humans

Valverde, Paloma; Healy, Eugene; Jackson, Ian J.; Rees, Jonathan; Thody, A. J.

doi:10.1038/ng1195-328

Cited by 906 publications

(728 citation statements)

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“…Some variants, such as V92M and V60L, were thought to be linked to red hair and pale skin (Valverde et al, 1995), and were later found in individuals with other types of normal pigmentation (Box et al, 1997;Koppula et al, 1997). R151C, R160W, and D294H have been linked to red hair and pale skin by most of the previous studies.…”

Section: Resultsmentioning

confidence: 98%

“…UV radiation was also found to increase the activity of these receptors in mouse melanoma cells (Chakraborty and Pawelek, 1993). In humans MC1R variants have been associated with sunsensitive skin types I and II (Valverde et al, 1995;Koppula et al, 1997), suggesting a predisposition to cancer in individuals with MC1R mutations. Specific variants that have been found to be associated with the red hair and pale skin phenotype; R151C, R160W and D294H (Box et al, 1997;Smith et al, 1998) were found to be significantly associated with cutaneous malignant melanoma (CMM) (Palmer et al, 2000).…”

Section: Introductionmentioning

confidence: 92%

“…In mammals the orthologue of the MC1R gene, the extension locus (e), was found mutated in those with red and yellow coat colours (Robbins et al, 1993;Vage et al, 1997). Studies on the molecular basis of the red hair and pale skin phenotype in humans have shown that the MC1R gene plays a role in this pigmentation type (Valverde et al, 1995;Box et al, 1997;Koppula et al, 1997;Smith et al, 1998;Rana et al, 1999). Various MC1R mutations have been identified in individuals with this and other pigment phenotypes.…”

Section: Introductionmentioning

confidence: 99%

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Four novel variants in MC1R in red-haired South African individuals of European descent: S83P, Y152X, A171D, P256S

John

Ramsay

2002

Hum. Mutat.

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Skin, hair and eye pigmentation is a polygenic multifactorial trait determined by the cumulative effects of multiple genetic variants and environmental factors. MC1R is one of the genes involved in pigmentation, and has been implicated in the red hair and pale skin trait in human Caucasoid individuals. This study was undertaken to investigate variants in the MC1R gene in Caucasoid individuals in South Africa, who are of European decent. Seven unrelated individuals were studied, all of whom were found to be either homozygous for a single mutation or compound heterozygous for two different mutations. We report four novel MC1R missense mutations: S83P, Y152X, A171D and P256S. This study supports the view that two mutations are necessary, but not necessarily sufficient, to give rise to the red hair and pale skin phenotype

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Four novel variants in MC1R in red-haired South African individuals of European descent: S83P, Y152X, A171D, P256S

John

Ramsay

2002

Hum. Mutat.

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“…Five receptors (MC-1R -MC-5R) have been cloned to date (Mountjoy et al, 1992) and MC-1R is expressed on human keratinocytes, melanocytes and melanoma cells (Donatien et al, 1992;De Luca et al, 1993;Bohm et al, 1999). Loss-of-function polymorphic variants exist (Valverde et al, 1995) and are associated with red-haired individuals who pigment poorly (Schiöth et al, 1999). Reports also suggest that MC-1R polymorphisms correlate with cutaneous melanoma (Box et al, 1997;Jiménez-Cervantes et al, 2001), although not all studies have confirmed this (Ichii-Jones et al, 1998).…”

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confidence: 99%

Anti-inflammatory and anti-invasive effects of α-melanocyte-stimulating hormone in human melanoma cells

et al. 2003

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a-Melanocyte stimulating hormone (a-MSH) is known to have pleiotrophic functions including pigmentary, anti-inflammatory, antipyretic and immunoregulatory roles in the mammalian body. It is also reported to influence melanoma invasion with levels of a-, b-and g-MSH correlated clinically with malignant melanoma development, but other studies suggest a-MSH acts to retard invasion. In the present study, we investigated the action of a-MSH on three human melanoma cell lines (HBL, A375-SM and C8161) differing in metastatic potential. a-melanocyte-simulating hormone reduced invasion through fibronectin and also through a human reconstructed skin composite model for the HBL line, and inhibited proinflammatory cytokine-stimulated activation of the NF-kB transcription factor. However, A375-SM and C8161 cells did not respond to a-MSH. Immunofluorescent microscopy and Western blotting identified melanocortin-1 receptor (MC-1R) expression for all three lines and MC-2R on HBL and A375-SM lines. Receptor binding identified a similar affinity for a-MSH for all three lines with the highest number of binding sites on HBL cells. Only the HBL melanoma line demonstrated a detectable cyclic adenosine monophosphate (cAMP) response to a-MSH, although all three lines responded to acute a-MSH addition ( þ (À)-N 6 -(2-phenylisopropyl)-adenosine (PIA)) with an elevation in intracellular calcium. The nonresponsive lines displayed MC-1R polymorphisms (C8161, Arg (wt) 151/Cys 151; A375-SM, homozygous Cys 151), whereas the HBL line was wild type. Stable transfection of the C8161 line with wild-type MC-1R produced cells whose invasion was significantly inhibited by a-MSH. From this data, we conclude that a-MSH can reduce melanoma cell invasion and protect cells against proinflammatory cytokine attack in cells with the wild-type receptor (HBL).

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“…It is also worth drawing attention to apparent discrepancies in the literature. First, studies relating phenotype to genotype need to take account of which alleles are thought to be important (1,38,39,(45)(46)(47)(48)(49)(50). If only some alleles are studied, then genuine associations may be missed; this indeed seems to be the case.…”

Section: The Diversity Of Mc1r Allelesmentioning

confidence: 99%

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

Rees

2000

Pigment Cell Research

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169

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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

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Variants of the melanocyte–stimulating hormone receptor gene are associated with red hair and fair skin in humans

Cited by 906 publications

References 15 publications

Four novel variants in MC1R in red-haired South African individuals of European descent: S83P, Y152X, A171D, P256S

Four novel variants in MC1R in red-haired South African individuals of European descent: S83P, Y152X, A171D, P256S

Anti-inflammatory and anti-invasive effects of α-melanocyte-stimulating hormone in human melanoma cells

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

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