Alternative titles; symbols
HGNC Approved Gene Symbol: MC1R
Cytogenetic location: 16q24.3 Genomic coordinates (GRCh38): 16:89,918,862-89,920,972 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.3 | [Analgesia from kappa-opioid receptor agonist, female-specific] | 613098 | 3 | |
| [Skin/hair/eye pigmentation 2, blond hair/fair skin] | 266300 | Autosomal recessive | 3 | |
| [Skin/hair/eye pigmentation 2, red hair/fair skin] | 266300 | Autosomal recessive | 3 | |
| {Albinism, oculocutaneous, type II, modifier of} | 203200 | Autosomal recessive | 3 | |
| {Melanoma, cutaneous malignant, 5} | 613099 | 3 | ||
| {UV-induced skin damage} | 266300 | Autosomal recessive | 3 |
Melanocyte-stimulating hormone (MSH; melanotropin) and adrenocorticotropic hormone (ACTH) regulate pigmentation and adrenocortical function, respectively. They are products of the same gene, the proopiomelanocortin (POMC; 176830) gene. MSH and ACTH bind to receptors that couple to heterotrimeric guanine nucleotide-binding proteins (G proteins) that activate adenylyl cyclase. Chhajlani and Wikberg (1992) isolated from human melanoma cells a cDNA for the melanocyte-stimulating hormone receptor. The cloned cDNA encoded a 317-amino acid protein with transmembrane topography characteristic of a G protein-coupled receptor. Mountjoy et al. (1992) cloned the murine and human MSH receptors and a human ACTH receptor (202200). These receptors were said to define a subfamily of receptors coupled to G proteins that may include the cannabinoid receptor (114610). The human MSH receptor was 76% identical to the amino acid sequence of the murine receptor, whereas the human ACTH receptor was approximately 39% identical with the human MSH receptor. MSHR mRNA was expressed in melanocytes, and ACTHR mRNA was expressed in adrenal tissue. Human MSHR was encoded predominantly by a 3-kb species. Using PCR with primers based on conserved areas of other members of 7-transmembrane G protein-linked receptors, Gantz et al. (1993) isolated several genes encoding an 'orphan' subfamily of receptors specific for melanocortins. One was identified as an alpha-MSH receptor, otherwise known as the melanocortin-1 (MC1) receptor (Mountjoy et al., 1992; Chhajlani and Wikberg, 1992).
Because of the potential immunogenicity of the MC1R gene, Lopez et al. (2007) evaluated its expression in uveal melanoma. Their results demonstrated that MC1R was expressed by uveal melanoma to a significantly greater extent than other melanoma markers. MC1R was found in 95% of melanoma tissues tested, including 1 liver metastasis. Even though MC1R was mainly located intracellularly, its cell surface expression could be promoted by cytokines, such as interferon-gamma (147570) and tumor necrosis factor-alpha (191160). The data supported MC1R as a new marker for the diagnosis of uveal melanoma and as a putative therapeutic target.
Chen et al. (2017) demonstrated a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC (red hair color, fair skin, and poor tanning ability) variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13 (612815), is essential for activating MC1R signaling, which triggers increased pigmentation, ultraviolet B-induced G1-like cell cycle arrest, and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1r(e/e)J mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, Chen et al. (2017) showed that pharmacologic activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis. Chen et al. (2017) concluded that their results highlighted a central role for MC1R palmitoylation in pigmentation and protection against melanoma.
By fluorescence in situ hybridization (FISH), Gantz et al. (1994) mapped the MC1R gene to 16q24.3. Magenis et al. (1994) confirmed the assignment of MSHR to 16q24 by FISH; by study of an intersubspecific backcross mapping panel, they assigned the gene to mouse chromosome 8.
Hair and Skin Pigmentation
In mice, mutations in either the Mc1r gene or the agouti gene (AGTI; 600201) affect the pattern of melanogenesis, resulting in changes in coat color (Jackson, 1993). Valverde et al. (1995) found MC1R gene sequence variants in over 80% of individuals with red hair and/or fair skin that tan poorly (see 266300) but in fewer than 20% of individuals with brown or black hair, and in less than 4% of those who showed a good tanning response. They interpreted the findings as indicating that MC1R is a control point in the regulation of pigmentation phenotype and that variations in this protein are associated with a poor tanning response. In this study, they amplified by PCR and directly sequenced the entire MC1R gene from 30 unrelated British or Irish individuals with different shades of red hair and a poor tanning response and in 30 control subjects of the same ethnicity with brown or black hair and good tanning response. In all, 9 different changes were identified; 8 of them clustered in a region of 42 amino acids, between the first cytoplasmic loop and the first extracellular loop, spanning the second transmembrane domain. The ninth change, asp294 to his (D294H; 155555.0001), was in the seventh transmembrane domain and was the most common, occurring in 16 of the individuals. Only 1 change in the coding region was found in 13 individuals, whereas 8 had 2 or more changes. They could establish that 7 of the 8 were compound heterozygotes for the changes. Although all these changes may not represent functionally significant variants, Valverde et al. (1995) noted that the most commonly observed variant, D294H, replaces an acidic residue with a basic one. The other frequent substitution, val92 to met (V92M; 155555.0002), together with the changes at codons 84 and 95, might be expected to alter the alpha-helix structure of the second transmembrane domain. The A64S substitution in the first cytoplasmic loop of the MC1R could affect the ability to stimulate adenylyl cyclase. The second transmembrane domain and the first extracellular loop represent a key region of the receptor. All 3 dominant gain-of-function mutations in the mouse found by Robbins et al. (1993) involved missense mutations in this region. The fairly common occurrence of multiple variants in the same allele was considered unusual, although not unprecedented (Savov et al., 1995).
Spritz (1995) pointed out puzzling features: one might expect mutations associated with red hair to be recessive; most of the red-head and fair-skinned individuals in their study were either heterozygous or had no identifiable mutations. In other species, amino acid substitutions within or adjacent to the second transmembrane domain of the MSHR polypeptide constitutively activate the corresponding receptors, resulting in dominant alleles. Alternatively, alleles that are associated with red coat color in Norwegian red cattle (Klungland et al., 1995) and in the red guinea pig are recessive and contain null mutations.
Smith et al. (1998) studied a general Irish population in which there was a preponderance of individuals with fair skin type; 75% carried a variant in the MC1R gene, with 30% carrying 2 variants. The R151C (155555.0004), R160W (155555.0005), and D294H variants were significantly associated with red hair. Importantly, all individuals harboring 2 of these 3 variants had red hair, although some red-haired individuals showed only 1 alteration. The D294H variant was similarly associated with red hair in a Dutch population, but was infrequent in red-haired subjects from Sweden. The D294H variant was also significantly associated with nonmelanoma skin cancer in a U.K. population.
To determine the functional significance of the MC1R mutations associated with red hair, Schioth et al. (1999) carried out transfection and binding studies. Expression in COS-1 cells of the D294H, R151C, and R160W mutations, as well as 2 other missense mutations, showed that these receptors were unable to stimulate cAMP production as strongly as the wildtype receptor in response to alpha-MSH stimulation. None of the mutant receptors displayed complete loss of alpha-MSH binding.
Flanagan et al. (2000) studied MC1R variation in 174 individuals from 11 large kindreds with a preponderance of red hair (266300) and an additional 99 unrelated redheads. They concluded 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 (155555.0006) variant, which is common in the Caucasian population, may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrated that heterozygotes for 2 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 or compound heterozygotes. The authors also presented evidence for a heterozygote effect on beard hair color, skin type, and freckling.
Akey et al. (2001) studied the contribution of the MC1R and P (OCA2; 611409) genes to interindividual variation in skin pigmentation in a Tibetan population. They genotyped 3 single-nucleotide polymorphisms (SNPs) in the MC1R gene and 2 SNPs in the P gene in 184 randomly ascertained Tibetan subjects, whose skin color was measured as a quantitative trait by reflective spectroscopy. Single-locus analyses failed to demonstrate an association between any of the 5 SNPs and skin pigmentation. However, when an epistatic model was applied to the data, a significant gene-gene interaction was identified between val92 to met in the MC1R gene and IVS13-15T-C in the P gene.
Healy et al. (2000) examined variants in the MC1R gene in individuals from Ireland and the U.K. Individuals with one variant allele were intermediate with regard to skin type and the ability to tan after repeated sun exposure between those with 2 variant alleles and those with none of the variants. Analysis for trend from 0 to 2 variants was highly significant, with little evidence of any nonlinear trend. Healy et al. (2000) suggested that the MC1R gene status therefore determines sun sensitivity in people without red hair.
Ephelides and solar lentigines are different types of pigmented skin lesions. Ephelides (freckles) appear early in childhood and are associated with fair skin type and red hair. Solar lentigines appear with increasing age and are a sign of photodamage. Both lesions are strong risk indicators for melanoma and nonmelanoma skin cancer. In a large case-control study, Bastiaens et al. (2001) studied patients with melanoma and nonmelanoma skin cancer and subjects without a history of skin cancer. Carriers of 1 or 2 MC1R gene variants had a 3- and 11-fold increased risk of developing ephelides, respectively (both P less than 0.0001), whereas the risk of developing severe solar lentigines was increased 1.5- and 2-fold (P = 0.035 and P less than 0.0001), respectively. These associations were independent of skin type and hair color, and were comparable in patients with and without a history of skin cancer. The population attributable risk for ephelides to MC1R gene variants was 60%, and a dosage effect was found between the degree of ephelides and the number of MC1R gene variants. As nearly all individuals with ephelides were carriers of at least 1 MC1R gene variant, the authors proposed that MC1R gene variants may be necessary to develop ephelides, and may play a less important role in the development of solar lentigines.
John and Ramsay (2002) reported 4 novel variants in MC1R in red-haired South African individuals of European descent.
In Jamaica there are persons who self-identify as black who have auburn/reddish hair, freckles, and a 'rust-colored' complexion (sometimes called 'red Ibos'). McKenzie et al. (2003) examined MC1R sequence and hair melanins in 4 Jamaican 'redheads.' Sequencing of the MC1R gene revealed that all of the redheads were compound heterozygotes for variants that were either known to or predicted to disrupt MC1R function. The melanin values were within the range seen in white UK individuals of equivalent MC1R status, suggesting that even on a different genetic background MC1R variants exert a significant phenotypic effect. McKenzie et al. (2003) concluded that red hair in this group (with West African ancestry) can be accounted for in terms of mutation of MC1R.
Rees (2004) stated that more than 65 human MC1R alleles with nonsynonymous changes had been identified, and that the evidence at hand suggested that many of them vary in their physiologic activity, such that a graded series of responses can be achieved on the basis of (i) dosage effects (of 1 or 2 alleles) and (ii) individual differences in the pharmacologic profile in response to ligand. Thus, a single locus, identified within a mendelian framework, can contribute significantly to human pigmentary variation. Despite a large number of murine coat-color mutations, only this 1 gene in humans was known to account for substantial variation in skin and hair color and in skin cancer incidence.
In 22 redheaded individuals with 2 or more MC1R variant alleles (R151C, R160W, and D294H) known to abolish receptor function, Mogil et al. (2005) found increased baseline pain tolerance and increased analgesic response after administration of the mu-opioid selective morphine metabolite, morphine-6-glucuronide (M6G), compared to controls. Experiments in Mc1r-null mice yielded similar results; in both humans and mice, the M6G/MC1R interaction was sex-independent.
Using immunofluorescence and ligand-binding studies, Beaumont et al. (2005) found that melanocytic cells exogenously or endogenously expressing MC1R showed strong surface localization of wildtype and D294H receptors, but markedly reduced cell surface expression of R151C, R160W, D84E (155555.0003), and I155T receptors. Variants weakly associated with red hair color, such as V60L, V92M, and R163Q, were expressed with normal or intermediate cell surface receptor levels. Beaumont et al. (2005) suggested that receptor localization, in addition to reduced receptor coupling activity, may also contribute to the genetic association between the MC1R variants and the red hair color phenotype.
Gerstenblith et al. (2007) reviewed 52 published studies that examined the allele frequency of MC1R polymorphisms in various human populations. There were large differences in the distribution of variants across populations, with a prominent difference between lightly and darkly pigmented individuals. Among Caucasian groups, there were 7 variants with significantly different allele frequencies.
Among 2,986 Icelanders, Sulem et al. (2007) carried out a genomewide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun, and freckling. The most closely associated SNPs from 6 regions were then tested for replication in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. Sulem et al. (2007) detected a 1-Mb region of strong linkage spanning 38 SNPs and containing the MC1R gene that was associated with red hair, skin sensitivity to sun, and freckles. SNPs within the region also showed a trend towards association with blond hair. The association signal was due to the previously reported SNPs rs1805007 (R151C; 155555.0004) and rs1805008 (R160W; 155555.0005). Analysis of allele frequencies suggested that both mutated alleles may have been at least weakly affected by recent positive selection.
Melanoma
Valverde et al. (1996) reported that certain variants of the MC1R gene are more common in individuals with melanoma (CMM5; 613099) than in control subjects and that this association is greater than the association between melanoma and skin type. MC1R variants in the second and seventh transmembrane domains were more common in melanoma cases than controls (chi square = 6.75, 1 d.f.; p = 0.0094) with a relative risk to carriers of variant alleles compared with normal homozygotes of 3.91. The D84E variant was only present in melanoma cases.
Palmer et al. (2000) studied the relationship between risk of melanoma and MC1R polymorphisms. They reported the occurrence of 5 common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals, as well as the relationship of these polymorphisms to such other risk factors as skin, hair, and eye color, freckling, and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of persons with CMM, whereas only 56% of the control individuals carried at least 1 variant (P less than 0.01), a finding independent of strength of family history of melanoma. Three 'active' alleles previously associated with red hair (R151C, R160W, and D294H) doubled CMM risk for each additional allele carried. No such independent association could be demonstrated with the V60L and D84E variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. Palmer et al. (2000) concluded that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype, and that these alleles may have also negated the protection normally afforded by darker skin coloring in some members of this white population.
Mutations in the CDKN2A gene (600160) are melanoma predisposition alleles with high penetrance, although they have low population frequencies. In contrast, variants of MC1R confer much lower melanoma risk but are common in European populations. To test for possible modifier effects on melanoma risk, Box et al. (2001) assessed 15 Australian CDKN2A mutation-carrying melanoma pedigrees for MC1R genotype. A CDKN2A mutation in the presence of a homozygous consensus MC1R genotype had a raw penetrance of 50%, with a mean age at onset of 58.1 years. When an MC1R variant allele was also present, the raw penetrance of the CDKN2A mutation increased to 84%, with a mean age at onset of 37.8 years (P = 0.01). The presence of a CDKN2A mutation gave a hazard ratio of 13.35, and a hazard ratio of 3.72 for MC1R variant alleles was also significant. The impact of MC1R variants on risk of melanoma was mediated largely through the action of the 3 common alleles, R151C, R160W, and D294H, associated with red hair, fair skin, and skin sensitivity to ultraviolet light.
Van der Velden et al. (2001) found that the MC1R variant R151C modified melanoma risk in Dutch families with melanoma. They concluded that the R151C variant is overrepresented in patients with melanoma from families with the p16-Leiden mutation (600160.0003). They suggested that the R151C variant may be involved in melanoma tumorigenesis in a dual manner, both as a determinant of fair skin and as a component in an independent additional pathway, because the variant contributed to increased melanoma risk even after statistical correction for its effect on skin type.
Bastiaens et al. (2001) presented findings indicating that MC1R gene variants are important independent risk factors for nonmelanoma skin cancer. A strong association between MC1R gene variants and fair skin and red hair was established, but when subjects were stratified by skin type and hair color, analyses showed that these factors did not materially change the relative risk of nonmelanoma skin cancer.
Landi et al. (2006) showed that MC1R variants are strongly associated with BRAF (164757) mutations in nonchronic sun-induced damage melanomas. In this tumor subtype, the risk for melanoma associated with MC1R is due to an increase in risk of developing melanomas with BRAF mutations. Landi et al. (2006) found that BRAF mutations were more frequent in nonchronic sun-induced damage melanoma cases with germline MC1R variants than in those with 2 wildtype MC1R alleles. When the authors categorized patients into 2 groups, homozygous MC1R wildtype versus all others, they found that BRAF mutations were 6 to 13 times as frequent in those with at least 1 MC1R variant allele compared to those with no MC1R variants. Four more tests for interaction between age and MC1R were not significant. Comparison of nonchronic sun-damaged Italian cases with 171 healthy Italian controls showed that the overall melanoma risk was higher by a factor of 3.3 (95% CI 1.5-6.9) in individuals with any MC1R variant allele compared to individuals with no variant alleles and that the risk increased with the number of variant MC1R alleles.
Perez Oliva et al. (2009) performed functional characterization of 6 MC1R missense mutations found in Spanish melanoma patients, 1 of which was found to be a functionally silent polymorphism. The 5 other mutations were associated with varying degrees of loss of function, ranging from moderate decreases in coupling to the cAMP pathway to nearly complete absence of functional coupling. Two of the variants were trafficked to the cell surface but were unable to bind agonists efficiently, whereas the other 3 variants had reduced cell surface expression due to retention in the endoplasmic reticulum.
Susceptibility to UV-Induced Sun Damage
Nakayama et al. (2006) identified 3 rare novel variants of the MC1R gene (155555.0007-155555.0009) among 995 individuals from 30 Asian and Oceanian populations. The variants were found only in East Asian populations that were geographically localized in relatively high latitudes, suggesting that the adaptation to ambient UV light intensity may play a role in shaping the geographic distribution of MC1R alleles in Asia and Oceania. Frequency of the V92M (155555.0002) variant was particularly high in Southeast Asia (0.43), which the authors postulated was due to demographic effects and migration.
Kappa-Opioid Analgesia
Mogil et al. (2003) noted that sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from kappa-opioid receptor (165196) agonists, a drug class reported to be clinically effective only in women. By QTL mapping followed by a candidate gene strategy using both mutant mice and pharmacologic tools, Mogil et al. (2003) demonstrated that the Mc1r gene mediates kappa-opioid analgesia (613098) in female mice only. This finding suggested that individuals with variants of the human MC1R gene associated with red hair and fair skin might also display altered kappa-opioid analgesia. Of 9 males and 5 females with 2 variant MC1R alleles (i.e., either homozygotes or compound heterozygotes), 3 were homozygous for R151C (155555.0004), 1 was homozygous for D294H (155555.0001), 6 were compound heterozygous for R151C and R160W (155555.0005), 2 were compound heterozygous for R151C/D294H, and 1 was compound heterozygous for R160W/V92M (155555.0002). Mogil et al. (2003) found that women with 2 variant MC1R alleles (see 155555.0004 and 155555.0005) displayed significantly greater analgesia from the kappa-opioid pentazocine than all other groups. They observed that skin type appeared to be a better proxy for MC1R genotype than hair color, as these effects reached significance for ischemic pain when light- versus dark-skinned women were compared, but did not do so when red-haired women were compared with women without red hair. This study demonstrated an unexpected role for the MC1R gene, verified that pain modulation in the 2 sexes involves neurochemically distinct substrates, and represented an example of a direct translation of a pharmacogenetic finding from mouse to human.
Modification of Oculocutaneous Albinism
King et al. (2003) pointed out that oculocutaneous albinism (OCA) can be produced by mutations at least 11 loci. They provided the first demonstration of a gene modifying the OCA phenotype in humans. Most individuals with OCA develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. In the average population, sequence variation in the MC1R gene is associated with red hair, but red hair is unusual in OCA. King et al. (2003) identified 8 probands with OCA2 (203200) who had red hair at birth. Mutations in the P gene were responsible for the classic phenotype of OCA2 in all 8, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the 6 of the 8 who continued to have red hair after birth. They illustrated one of their patients, an 18-year-old female of northern European ancestry with red hair. She carried a trp679-to-cys mutation in the P gene (W679C; 611409.0009) from her mother and an asn489-to-asp mutation (N489D; 611409.0010) in the P gene from her father. At the MC1R locus she was a compound heterozygote for arg151 to cys (R151C; 155555.0004) and arg160 to trp (R160W; 155555.0005).
Rompler et al. (2006) identified coat-color polymorphisms in the mammoth (Mammuthus primigenius) Mc1r gene. One of these, arg67 to cys, is carried at the homologous sequence position by light-colored populations of the beach mouse (Peromyscus polionotus leucocephalus). Functional tests and crossing experiments revealed both a reduction in basal and induced activity highly similar to that observed for the mammoth MC1R protein and a strong association between this amino acid polymorphism and adaptive coat color phenotype (Hoekstra et al., 2006).
The MC1R gene regulates pigmentation in human and other vertebrates. Variants of MC1R with reduced function are associated with pale skin color and red hair in humans of primarily European origin. Lalueza-Fox et al. (2007) amplified and sequenced a fragment of the MC1R gene (mc1r) from 2 Neanderthal remains. Both specimens had a mutation (arg307 to gly) that was not found in approximately 3,700 modern humans analyzed. Functional analyses showed that this variant reduces MC1R activity to a level that alters hair and/or skin pigmentation in humans. The impaired activity of this variant suggested that Neanderthals varied in pigmentation levels, potentially on the scale observed in modern humans. Lalueza-Fox et al. (2007) concluded that inactive MC1R variants evolved independently in both modern humans and Neanderthals.
The brown mutation in blind Mexican cave fish results in reduced pigmentation of the eye and reduced number and size of melanophores of the skin. Gross et al. (2009) identified 2 independent genetic changes in the coding sequence of the Mc1r gene in 2 geographically separated populations of Mexican cave fish with the brown mutant phenotype.
In the mouse, the coat color extension locus has been identified with the MSH receptor gene. A truncated MSH receptor leads to light coat color, while activating mutations of the receptor lead to dark coat color (Robbins et al., 1993).
Joerg et al. (1996) demonstrated that red coat color in Holstein cattle is associated with a deletion in the MSHR gene. Chestnut (red) coat color in horses was shown by Johansson et al. (1994) to cosegregate with polymorphism at the MSHR locus. Marklund et al. (1996) demonstrated that polymorphism consists of a single missense mutation, ser83phe, in the MC1R allele associated with the chestnut color. The substitution occurs in the second transmembrane region, which apparently plays a key role in the molecule since substitutions associated with coat color variance in mice and cattle as well as red hair and fair skin in humans are found in this part of the molecule.
Loss of MC1R function in nonhuman mammals results in red or yellow hair pigmentation. Healy et al. (2001) demonstrated that a mouse bacterial artificial chromosome (BAC) containing Mc1r rescued loss of Mc1r in transgenic mice, and overexpression of the receptor suppressed the effect of the endogenous antagonist, agouti protein (ASIP; 600201). The human receptor also efficiently rescued Mc1r deficiency and, in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles (D294H, 155555.0001; R151C, 155555.0004; and R160W, 155555.0005) were engineered into the BAC, and each had reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of alpha-MSH-deficient mice and humans in conjunction with these data suggested to the authors that red hair may not be the null phenotype of MC1R.
Eizirik et al. (2003) studied the molecular genetics and evolution of melanism in the cat family. Melanistic coat coloration occurs as a common polymorphism in 11 of 37 felid species and reaches high population frequency in some cases but never achieves complete fixation. Eizirik et al. (2003) mapped, cloned, and sequenced the cat homologs of 2 putative candidate genes for melanism, ASIP and MC1R, and identified 3 independent deletions associated with dark coloration in 3 different felid species. Association and transmission analyses revealed that a 2-bp deletion in the ASIP gene specifies black coloration in domestic cats, and 2 different in-frame deletions in the MC1R gene are implicated in melanism in jaguars and jaguarundis. Melanistic individuals from 5 other felid species did not carry any of these mutations, implying that there are at least 4 independent genetic origins for melanism in the cat family. The inferred multiple origins and independent historical elevation in population frequency of felid melanistic mutations suggested the occurrence of adaptive evolution of this visible phenotype in a group of related free-ranging species.
An MC1R arg306-to-ter (R306X) mutation was shown to cause a completely red or yellow coat color in certain dog breeds such as Irish setters, yellow Labrador retrievers, and golden retrievers (Newton et al., 2000; Everts et al., 2000). Black mask is a characteristic pattern in which red, yellow, tan, fawn, or brindle dogs exhibit a melanistic muzzle which may extend up onto the ears. Melanistic mask is inherited in several dog breeds as an autosomal dominant trait, and appears to be a fixed trait in a few breeds. Schmutz et al. (2003) examined the amino acid sequence of the MC1R gene in 17 dogs with melanistic masks from 7 breeds, 19 dogs without melanistic masks, and 7 dogs in which their coat color made the mask difficult to distinguish. All dogs with a melanistic mask had at least one copy of a valine substitution for methionine at amino acid 264 (M264V) and none was homozygous for the R306X mutation.
Nachman et al. (2003) described the molecular changes underlying adaptive coat color variation in a natural population of rock pocket mice. These mice are generally light-colored and live on light-colored rocks. However, populations of dark (melanic) mice are found on dark lava, and this concealing coloration provides protection from avian and mammalian predators. Nachman et al. (2003) conducted association studies by using markers in candidate pigmentation genes and discovered 4 mutations in the Mc1r gene that seem to be responsible for adaptive melanism in one population of lava-dwelling pocket mice. However, another melanic population of these mice on a different lava flow showed no association with Mc1r mutations, indicating that adaptive dark color had evolved independently in this species through changes at different genes.
'Tawny' is an autosomal recessive coat color found in a wild population of Japanese mice and maintained in an inbred laboratory strain. Tawny mice show light yellowish brown coloration on the dorsal region, with a white belly and black eyes. Wada et al. (2005) identified 6 nucleotide changes in the Mc1r gene in tawny mice, leading to 3 amino acid substitutions. They determined that one of the substitutions, trp252 to cys, is unique to tawny mice and is therefore responsible for the tawny coat color.
Natural populations of beach mice exhibit a characteristic color pattern, relative to their mainland conspecifics, driven by natural selection for crypsis. Hoekstra et al. (2006) identified a derived, charge-changing amino acid mutation in the melanocortin-1 receptor (R65C) in beach mice that decreases receptor function. In genetic crosses, allelic variation at Mc1r explains 9.8% to 36.4% of the variation in 7 pigmentation traits determining color pattern. The derived Mc1r allele is present in Florida's Gulf Coast beach mice but not in Atlantic coast mice with similar light coloration, suggesting that different molecular mechanisms are responsible for convergent phenotypic evolution. Hoekstra et al. (2006) concluded that they were able to link a single mutation in the coding region of a pigmentation gene to adaptive quantitative variation in the wild.
D'Orazio et al. (2006) showed that ultraviolet light potently induced expression of melanocyte-stimulating hormone (MSH; 176830) in keratinocytes, but failed to stimulate pigmentation in the absence of functional MC1R in red/blonde-haired mice possessing an inactivating mutation of the MSH receptor (Mclr(e/e) mice, formerly known as extension). However, pigmentation could be rescued by topical application of the cyclic AMP agonist forskolin, without the need for ultraviolet light, demonstrating that the pigmentation machinery is available despite the absence of functional MC1R. This chemically induced pigmentation was protective against ultraviolet light-induced cutaneous DNA damage and tumorigenesis when tested in the cancer-prone, xeroderma pigmentosum complementation group C (278720)-deficient genetic background. D'Orazio et al. (2006) concluded that these data emphasize the essential role of intercellular MSH signaling in the tanning response, and suggest a clinical strategy for topical small-molecule manipulation of pigmentation.
Jackson et al. (2007) found that the pigmentation pattern of wildtype mice and transgenic mice expressing human MC1R appeared identical. However, human MC1R was more sensitive to the exogenous ligand alpha-MSH than was mouse Mc1r. Mouse Mc1r, but not human MC1R, elicited eumelanin synthesis in the absence of ligand. Mouse Asp blocked activation of human MC1R, but it did not exaggerate the inhibition of MC1R toward reverse signaling as it did with mouse Mc1r. Both human and mouse MC1R showed ligand-independent signaling in transfected cells.
Melanism in the gray wolf, Canis lupus, is caused by mutation in the K locus, which encodes a beta-defensin protein (DEFB103A; 606611) that acts as an alternative ligand for Mc1r. Anderson et al. (2009) showed that the melanistic K locus mutation in North American wolves derives from past hybridization with domestic dogs, has risen to high frequency in forested habitats, and exhibits a molecular signature of positive selection. The same mutation also causes melanism in the coyote, Canis latrans, and in Italian gray wolves. Anderson et al. (2009) concluded that their results demonstrated how traits selected in domesticated species can influence the morphologic diversity of their wild relatives.
Mitra et al. (2012) introduced a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF(V600E), into mice carrying an inactivating mutation in the Mc1r gene, Mc1r(e/e), which results in a phenotype analogous to red hair/fair skin humans. The authors observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet radiation-independent carcinogenesis, Mitra et al. (2012) introduced an albino allele, which ablates all pigment production on the Mc1r(e/e) background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r(e/e) mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1r(e/e) mouse skin. Mitra et al. (2012) concluded that these data suggested that the pheomelanin pigment pathway produces ultraviolet radiation-independent carcinogenic contributions to melanogenesis by a mechanism of oxidative damage. The authors further concluded that although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.
Valverde et al. (1995) found that the asp294-to-his (D294H) substitution was the most commonly observed variant in the MC1R gene in individuals with different shades of red hair, with fair skin, and poor tanning response (266300). It was present alone in 9 individuals and in combination with another variant on the same allele or on the other allele in 7 others with different shades of red hair, but in none with dark brown/black hair, in a study that involved 30 individuals in these 2 classes.
Valverde et al. (1995) found that one of the most frequent mutations associated with light and deep red hair and a skin with a tendency to sunburn (266300) was val92 to met (V92M). This mutation was thought to alter the alpha-helix structure of the second transmembrane domain of the MSH receptor. Xu et al. (1996) found the V92M variant in 7 of 11 cases of skin type I (always burn, never tan). They found, furthermore, that when the val92-to-met variant was expressed in COS-1 cells, the endogenous hormone had approximately 5 times lower potency in displacing a radiolabeled analog of alpha-MSH as compared to the wildtype receptor. In mammals, the relative amounts of eumelanin (black pigment) and pheomelanin (red pigment) are regulated by action of alpha-MSH on its receptor; the higher the affinity of alpha-MSH to its receptor the greater the eumelanin level.
This polymorphism was found by Koppula et al. (1997) in 6.6% of individuals they studied, predominantly those with blue eyes and blond hair. It was found in both heterozygous and homozygous states in individuals with type I skin. The D84E allele (155555.0003) was found in 1 individual with skin type I; this person also had the V92M allele and thus was a compound heterozygote.
Nakayama et al. (2006) identified the V92M variant in 488 (0.43) of 1,140 alleles from 16 Southeast Asian populations. The authors postulated that the increased frequency was due to demographic effects and migration.
Valverde et al. (1996) noted that a particular allele, asp84 to glu (D84E), was present in 23% of the melanoma (CMM5; 613099) subjects but was absent from controls. The D84E allele accounted for most of the association with melanoma. Valverde et al. (1996) reported that the aspartate at codon 84 is highly conserved throughout the melanocortin receptor family and in other G protein-coupled receptors. They noted, however, that the functional significance of the mutation was not clear and that it was not possible to determine if the mutation was the direct cause of melanoma.
Frandberg et al. (1998) identified an R151C variant of the MC1R gene in genomic DNA of a person with red hair and light skin of type I (always burn, never tan) (266300). The R151C variant of MC1R bound to radiolabeled analog of alpha-MSH with identical affinity as wildtype MC1R but could not be stimulated to produce cyclic AMP. The mutation rendered human MC1R completely nonfunctional.
In a study of 24 redheaded individuals (12 male and 12 female) and 24 nonredheaded controls, Mogil et al. (2003) found that 5 women with 2 variant MC1R alleles, all of whom had red hair, displayed significantly greater analgesia from the kappa-opioid pentazocine (613098) than all other groups; 3 of the women were homozygous for R151C and 2 were compound heterozygous for R151C and R160W (155555.0005) (Mogil, 2003).
King et al. (2003) found mutation in the MC1R gene to be responsible for red hair (rather than yellow/blond) in 6 patients with oculocutaneous albinism type 2 (OCA2; 203200). One of the patients was compound heterozygous for R151C and R160W (155555.0005) in the MC1R gene, as well as for 2 mutations in the P gene (see 611409.0009).
Nakayama et al. (2006) identified the R151C variant in 1 of 1,990 alleles from 30 Asian and Oceanian populations. The allele was from an individual of the East Asian Manchu population. In vitro functional expression studies showed that the R151C variant protein retained some residual ability to stimulate cAMP production, in contrast to previous reports that found that the R151C change resulted in complete loss of function.
In a discovery sample of 2,986 Icelanders and replication samples of 2,718 Icelanders and 1,214 Dutch, Sulem et al. (2007) found association of the T allele of MC1R SNP rs1805007 (R151C) with red hair (discovery OR = 12.47, P = 2.0 x 10(-142)), with skin sensitivity to sun (discovery OR = 2.94, P = 1.8 x 10(-55)), and with freckling (discovery OR = 4.37, P = 1.2 x 10(-96)).
In a case-control study of 272 patients with late-onset Parkinson disease (PD; 168600) and 1,185 controls from 2 U.S. health professional study cohorts, Gao et al. (2009) found an association between the cys151 SNP of the MCR1 gene and increased risk of PD relative to the arg151 SNP (relative risk of 3.15 for the cys/cys genotype). Noting that melanin, like dopamine, is synthesized from tyrosine, and that PD is characterized by the loss of neuromelanin-containing neurons in the substantia nigra, Gao et al. (2009) postulated a link between pigmentation and development of PD.
Dong et al. (2014) did not find a significant association between the R151C MC1R variant and Parkinson disease in 2 large datasets of 808 PD patients and 1,623 controls and 5,333 PD patients and 12,019 controls. All the participants were non-Hispanic whites.
Tell-Marti et al. (2015) did not find a significant association between the R151C MC1R variant and Parkinson disease among 870 Spanish PD patients and 736 controls.
In an Irish population, Smith et al. (1998) found an association between the arg160-to-trp (R160W) variant of the MC1R gene and red hair and/or fair skin (266300).
In a study of 24 redheaded individuals (12 male and 12 female) and 24 nonredheaded controls, Mogil et al. (2003) found that 5 women with 2 variant MC1R alleles, all of whom had red hair, displayed significantly greater analgesia from the kappa-opioid pentazocine (613098) than all other groups; 3 of the women were homozygous for R151C (155555.0004) and 2 were compound heterozygous for R151C and R160W (Mogil, 2003).
See 155555.0004 and King et al. (2003).
In a discovery sample of 2,986 Icelanders and replication samples of 2,718 Icelanders and 1,214 Dutch, Sulem et al. (2007) found association of the T allele of MC1R SNP rs1805008 (R160W) with red hair (discovery OR = 7.86, P = 4.2 x 10(-95)), with skin sensitivity to sun (discovery OR = 2.30, P = 1.8 x 10(-43)) and with freckling (discovery OR = 2.63, P = 2.8 x 10(-60)).
Dong et al. (2014) did not find a significant association between the R160W MC1R variant and Parkinson disease in 2 large datasets of 808 PD patients and 1,623 controls and 5,333 PD patients and 12,019 controls. All the participants were non-Hispanic whites.
By sequencing the entire MC1R gene in 870 Spanish patients with Parkinson disease (PD; 168600) and 736 controls, Tell-Marti et al. (2015) found that the R160W MC1R variant was marginally associated with PD (odds ratio of 2.10, p = 0.009, Bonferroni-corrected p = 0.063). The mode of inheritance could not be determined because there were no homozygous carriers, only heterozygous carriers.
Lubbe et al. (2016) found no association of the MC1R variant R160W and PD in a cohort of 5,944 PD cases and 4,642 controls collected through the International Parkinson Disease Genomics Consortium (IPDGC). In a reply to Lubbe et al. (2016), Tell-Marti et al. (2016) pointed out that the minor allele frequency (MAF) of the R160W variant in the Spanish population is lower than that found in other European populations, and that different subpopulation stratification in the study of Lubbe et al. (2016) could be limiting the replication of their findings. They also noted discrepancies in the MAF of R160W in Greek control populations in skin cancer and IPDGC studies. Tell-Marti et al. (2016) concluded that attempts to validate their association findings of MC1R and PD be performed in larger and homogenous populations in which control samples specifically not include subjects with cutaneous melanoma or a family history of it, so as to avoid an overrepresentation of risk variants in controls.
Box et al. (1997) reported an association between the val60-to-leu (V60L) variant of the MC1R gene and blond/light brown hair and/or fair skin (266300).
In 2 of 1,990 alleles from 30 Asian and Oceanian populations, Nakayama et al. (2006) identified a 3-bp deletion in the MC1R gene, resulting in a deletion of phe147 in a highly conserved area in the second intracellular loop region. Both alleles were found in the Ewenki population of East Asia. In vitro functional expression studies showed that the variant protein was virtually unresponsive to MSH stimulation (266300).
In 2 of 1,990 alleles from 30 Asian and Oceanian populations, Nakayama et al. (2006) identified a 470C-T transition in the MC1R gene, resulting in a thr157-to-ile (T157I) substitution in a highly conserved area in the second intracellular loop region. The 2 alleles were found in the East Asian Han and Manchu populations. In vitro functional expression studies showed that the T157I variant had significantly decreased activity (266300).
In 1 of 1,990 alleles from 30 Asian and Oceanian populations, Nakayama et al. (2006) identified a 475C-A transversion in the MC1R gene, resulting in a pro159-to-thr (P159T) substitution in the second intracellular loop region. The allele was found in the East Asian Manchu population. In vitro functional expression studies showed that the P159T variant had significantly decreased activity (266300).
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