Loss of Function Mutations of the Human Melanocortin 1 Receptor Are Common and Are Associated with Red Hair

Schiöth, Helgi B.; Phillips, Siôn R.; Rudzish, Richard; Birch‐Machin, Mark A.; Wikberg, Jarl E. S.; Rees, Jonathan

doi:10.1006/bbrc.1999.0935

Cited by 226 publications

(209 citation statements)

References 22 publications

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“…Additionally, a number of substitutions outside the membrane domains are known to affect coloration in, for example, mice, mammoths, and humans (Schioth et al. 1999; Hoekstra et al. 2006; Rompler et al.…”

Section: Discussionmentioning

confidence: 99%

“…1993) or red hair of humans (Schioth et al. 1999). This basic pigmentation is further modified in many animals, where individuals of different breeds that are homozygous for the recessive e allele of the MC1R show a range of coat colors from red through cream‐colored to white (Schmutz et al.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the MC1R gene have been shown to induce a change in pigmentation in humans (Schioth et al. 1999) as well as in domestic animals including pigs, cows, chickens, horses, and dogs (Klungland et al. 1995; Marklund et al.…”

Section: Introductionmentioning

confidence: 99%

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Born blonde: a recessive loss‐of‐function mutation in the melanocortin 1 receptor is associated with cream coat coloration inAntarctic fur seals

Peters

Humble

Kröcker

et al. 2016

Ecology and Evolution

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Although the genetic basis of color variation has been extensively studied in humans and domestic animals, the genetic polymorphisms responsible for different color morphs remain to be elucidated in many wild vertebrate species. For example, hypopigmentation has been observed in numerous marine mammal species but the underlying mutations have not been identified. A particularly compelling candidate gene for explaining color polymorphism is the melanocortin 1 receptor (MC1R), which plays a key role in the regulation of pigment production. We therefore used Antarctic fur seals (Arctocephalus gazella) as a highly tractable marine mammal system with which to test for an association between nucleotide variation at the MC1R and melanin‐based coat color phenotypes. By sequencing 70 wild‐type individuals with dark‐colored coats and 26 hypopigmented individuals with cream‐colored coats, we identified a nonsynonymous mutation that results in the substitution of serine with phenylalanine at an evolutionarily highly conserved structural domain. All of the hypopigmented individuals were homozygous for the allele coding for phenylalanine, consistent with a recessive loss‐of‐function allele. In order to test for cryptic population structure, which can generate artefactual associations, and to evaluate whether homozygosity at the MC1R could be indicative of low genome‐wide heterozygosity, we also genotyped all of the individuals at 50 polymorphic microsatellite loci. We were unable to detect any population structure and also found that wild‐type and hypopigmented individuals did not differ significantly in their standardized multilocus heterozygosity. Such a lack of association implies that hypopigmented individuals are unlikely to suffer disproportionately from inbreeding depression, and hence, we have no reason to believe that they are at a selective disadvantage in the wider population.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Born blonde: a recessive loss‐of‐function mutation in the melanocortin 1 receptor is associated with cream coat coloration inAntarctic fur seals

Peters

Humble

Kröcker

et al. 2016

Ecology and Evolution

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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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“…In contrast, red hair is caused by a mutation of the melanocortin-1 receptor. [1][2][3] People with this mutation produce pheomelanin, which is yellow-red and accounts for the red hair and fair complexion consequent to defective melanocortin receptors.…”

mentioning

confidence: 99%

Red hair and anesthetic requirement

Sessler

2015

Can J Anesth/J Can Anesth

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Loss of Function Mutations of the Human Melanocortin 1 Receptor Are Common and Are Associated with Red Hair

Cited by 226 publications

References 22 publications

Born blonde: a recessive loss‐of‐function mutation in the melanocortin 1 receptor is associated with cream coat coloration inAntarctic fur seals

Born blonde: a recessive loss‐of‐function mutation in the melanocortin 1 receptor is associated with cream coat coloration inAntarctic fur seals

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

Red hair and anesthetic requirement

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