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Role of MC1R Gene on Body Coat Colour

Sidharth Prasad Mishra Chinmoy Mishra Reshma Saikhom Parthasarathi Swain Sasmita Panda Devi Prasanna Swain
Vol 7(5), 36-49

Mammalian pigmentation is guided by the melanocortin-1 receptor which depends on relative amount of pheomelanin and eumelanin. In the melanogenesis pathway the melanocortin-1-receptor (alpha melanocyte stimulating hormone receptor, MC1R) is responsible for the primary switch of pheomelanin for developing red to yellow pigment to eumelanin for black to brown pigment. In mammals, the difference in base colour are attributed due to mutations in the MC1R gene, also known as extension locus, historically codes for three alleles black (ED), red (e) and wild-type (E+) showed that there is existence of another allele E1. The extension alleles were assumed to be dominance in a descending order as ED> E+> e> E1. The wild-type allele (E+) having a 954 bp long coding sequence and encodes 317 Amino-acid in the full length MC1R gene. In the MC1R gene 150 bp upstream the ATG codon codes to the minimal gene promoter for the melanocyte-specific gene transcription. The MC1R protein, the amino acid similarity varied between 74.0% (mouse vs. dog) and 83.6% (cattle vs. dog). For MC1R, a comparison of nucleotide sequences similarity ranges between 75.1% (mouse vs. cattle) and 85.3% (pig vs. cattle).

Keywords : MC1R Allele Receptor Position SNPs Species


Mammalian pigmentation is guided by the melanocortin-1 receptor which depends on relative amount of pheomelanin and eumelanin. In the melanogenesis pathway the melanocortin-1-receptor (alpha melanocyte stimulating hormone receptor, MC1R) is responsible for the primary switch of pheomelanin for developing red to yellow pigment to eumelanin for black to brown pigment. Both the melanins are produced by neural crest-derived melanocytes in the skin and hair. It is owned by a biosynthetic pathway where tyrosinase acts as a rate limiting enzyme. High level of tyrosinase activity supports the eumelanin production and low level favors the synthesis of pheomelanin. Numerous experimental finds had been established in several laboratory and domestic animals that mutation at different region of MC1R gene causes either light or dark phenotypes for mouse by Barsh(1996), dog by Newton(2000), pig by Kijas (1998), horse by Marklund(1996), fox by Vage(1997) and chicken by Takeuchi(1997). In all experiments, it had been developed that dominant mutations are associated with a gain of MC1R function and results into dark colour while recessive mutation are associated with a reduction or loss of MC1R function and results in light dark colour. With the change in environmental condition both birds and mammals developed a intraspecific colour variation because of MC1R gene as studied in bananaquit by Theron et al., 2001, lesser snow goose and arctic skua by Mundy et al., 2003, jaguar and jaguarundi, Eizirik et al., 2003, black bear by Ritland et al., 2001, pocket mouse by Nachman et al., 2003. In contrast to it several other studies have failed to establish association between MC1R genotype and intraspecific colour variation (Kerns et al., 2003, MacDougall-Shackleton et al., 2003, Mundy and Kelly, 2003).

MC1R is responsible for regulating the hormone α-melanocyte stimulating hormone, (α-MSH), which is involved in pigment production (Barsh, 1996). MC1R has known effects on pigments in many animals. In jaguars, Panthera onca, and jaguarundis, Puma yagouaroundi, a dominant mutation of MC1R is responsible for melanism, the overproduction of eumelanin. However, melanism due to MC1R in domestic cats, Felis catus, follows a recessive inheritance pattern (Eizirik et al., 2003). By contrast, repression of MC1R can lead to lack of pigment, as in the case of the Kermode bear, Ursus americanus kermodei, which is a white colour morph of the black bear. The lack of eumelanin is caused by a recessive mutation at codon 298, replacing tyrosine with cytosine (Ritland et al., 2001). As with the case of the white tiger, the kermode bear is not an albino. In mammals, the difference in base colour are attributed due to mutations in the MC1R gene, also known as extension locus, historically codes for three alleles black (ED), red (e) and wild-type (E+) but Hulsman et al., 2014, showed that there is existence of another allele E1. The extension alleles were assumed to be dominance in a descending order as ED> E+> e> E1. The wild-type allele (E+) having a 954 bp long coding sequence and encodes 317 Amino-acid full length MC1R gene and produces a functional receptor that responds to both the α-melanocyte-stimulating hormone (α-MSH) ligand and its antagonist, agouti-signaling protein (ASP). So, it produces a variety of colour (Schioth et al., 2005). The ED allele caused by a single base pair amino-acid substitution (T296C) from leucine to proline as point mutation, creates an active receptor that results in eumelanin production most likely because of α-MSH ligand binding mimicry. By RFLP PCR analysis, Hulsman et al., 2014, illustrated that ED allele is identified by the substitution of cytosine to thymine, producing a 59 bp digested fragment with an appearance of new restriction site for ACiI.

Comparative Organization of MC1R Gene

Receptors of melanocortins are encoded by a gene family consisting of five members (MC1R–MC5R) given by Schioth, 2005. The encoded receptors bind four ligands: α-, β- and γ-melanocyte-stimulating hormone (α-,β-,γ-MSH) and the adrenocorticotropic hormone (ACTH). Among them MC1R binds to α-MSH, while MC2R binds to ACTH. Expression of the MCR genes is tissue-specific: MC1R is mainly expressed in melanocytes, MC2R in the adrenal cortex, MC3R and MC4R in the nervous system, and MC5R in sebaceous glands and other tissues, e.g. the brain, muscles, lung and kidney (Yang, 2011). The MCR genes contain only a single exon and the encoded number of amino acids varies from 296 in MC2R discovered by Webb, 2009 to 332 in MC4R by Tarnow, 2003. All these genes are located on autosomes. Some of them (MC2R, MC4R and MC5R) are located on a single chromosome: 18 in humans and the mouse postulated by Ringholm, 2004; 24 in cattle and 1 in the dog observed by Schmutz, 2012. In the case of the pig karyotype, the location is slightly different, since the MC1R, MC2R and MC5R genes reside on chromosome 6, but not MC4R, which is not systemic with MC2R and MC5R. This difference reflects chromosome rearrangements which took place during pig karyotype evolution (Goureau et al., 1996). A comparison of the coding sequences of the two most frequently studied MCR genes (MC1R and MC4R) revealed a higher evolutionary conservatism of the MC4R protein. In the case of the MC1R protein, the amino acid similarity varied between 74.0% (mouse vs. dog) and 83.6% (cattle vs. dog), while for MC4R, it varied between 90.7% (mouse vs. cattle) and 96.1% (pig vs. dog) (Dessinioti, 2011). A comparison of nucleotide sequences revealed practically the same level of similarity. For MC1R, it ranged between 75.1% (mouse vs. cattle) and 85.3% (pig vs. cattle), while for MC4R, it was between 84.0% (mouse vs. cattle) and 91.3% (human vs. pig). Knowledge on the genetic variants of melanocortin receptor genes and their phenotypic effects is most advanced for the MC1R and MC4R genes and to a lesser extent for MC3R (Loos, 2011).

Melanocyte Promoter Region for MC1R Gene

In the MC1R gene 150 bp upstream the ATG codon codes to the minimal gene promoter for the melanocyte-specific gene transcription. The characterization of the 5′-flanking region of the human MC1R has been carried out by Moro et al., 1999. He had discovered that about 3 kb of the human genomic sequences upstream the MC1R start codon, from -282 to -3200 and the minimal promoter region between the nucleotides -517 and -282 (Dessinioti, 2011). However, the activity of all the analyzed constructs showed similar promoter activity in both MC1R expressing and non expressing cells. The MC1R gene promoter region defined from the 150 bp upstream of the initiation codon. The human MC1R gene revealed multiple transcription initiation sites spread over a region of about 600 nucleotides ranging from -344 to -936 (Rouzaud, 2003 and Moro et al., 1999). Stefania, 2008 identified the melanocyte-specific cis promoter region in the DNA sequence for the 5′ untranslated region (5′-UTR) of the messenger RNA by tissue specific DNA protein complexes down-stream of the initiation of transcription. Internal promoters of the RNA polymerase III transcribed genes and from complexes assembled on the enhancer sequences that are often located at the 3′ of the gene, several RNA polymerase II transcribed genes have cis-elements located in the genomic region transcribed in the 5′- UTR and described as internal promoter. The transcription of macrophage IGF-I exon 1 is positively regulated by the 5′-UTR region (Wynes, 2005). Likewise, the CD28 gene is transcriptionally regulated by cis-sequences located in the first exon upstream of the initiation codon (Lin, 2001).

Structure of MC1R Gene

Colour variation is known to influence temperature regulation in variety of ectoderms (Eves and Haycock, 2010). The function of melanin is remarkably conserved in reptile’s pigment cell morphology as compared to that of mammals and birds. Reptiles have three important cell layers for pigment production. The layer closest to the epidermis consists of pigment-containing xanthophile cells that generate yellow or orange colors. The middle layer consists of iridophore cells that produce structural colours through the reflective properties of the cells. Finally, the deepest pigment cell layer produces melanin, and the overall darkness of the body is largely a consequence of the amount of melanin deposited by these melanophores (Everts et al., 2000). Unlike the mammals and birds, MC1R gene rather than acting as a switching between the two types of melanin is responsible for production of eumelanin. Inspite of these differences, changes in the production and dispersion of melanin granules are ultimately responsible for changes in the dorsal colour of reptiles (Honan, 2008). The length of MC1R gene is different among the species: in the phrynosomatid lizards H. maculate, P. platyrhinos, S. undulatus and U. stansburiana it is of 948 bp while in T. sirtalis and A. inornata is of 945 bp. But in A. pulchra, the first extracellular region of the gene is highly divergent from the other species has two start codon that were within the same frame (Sturm, 2003). However, an intervening stop codon suggests that only one start codon is functional, resulting in a gene length of 921 bp. In addition to the strong association between MC1R and colour, there is absence of evident population structure in the sample of A. inornata. It was evidenced that substitution of amino acid at position 170 which is located in the fourth transmembrane domain affected the colour of the species (Schioth et al., 2005). There was a well observed finding that the level of linkage disequilibrium at MC1R gene in the blanched colour sample was totally different from that of wild type colour sample. In fact, at the position 170 the isoleucine residue is associated with a single haplotype (T – isoleucine-TC) which is usually found in the wild type sample while the threonine in the position is associated with at least four haplotype that results into nearly fixation of T-isoleucine-TC haplotype in the blanched sample (Le Pape et al., 2009). This blanched phenotype with light coloured substrate was developed because of the colonization of these lizards into the geographically restricted habitat. In contrast to the substitution of amino acid at site 170 is not a specific residue known to affect colour in other species as a number of transmembrane mutations are known to result in colour change in other taxa though these are subjected to highly conserved (Ritland et al., 2001, Theron et al., 2001).

The recessive allele (e) leads to the production of only pheomelanin as deletion of guanine takes place in the position 310 because of a frameshift mutation. By this it creates a prematurely terminated, nonfunctional receptor protein of 155 amino-acid with only three putative transmembrane domains. Eves, 2010 revealed that E1 allele was characterized by a 12 bp duplicated sequence in position 669. This new bovine allele led to four amino acid (gly-ile-ala-arg) duplication within the 3rd intracellular loop of the receptor at the position 224 to 227.

Different SNPs of MC1R Gene

Ritland, 2001 illustrated that MC1R gene of 793 bp long were amplified in a multiplex PCR which were performed on chelex extracted DNA or on preserved lymphocyte on FTA paper. A fragment of 1648 bp coding sequence amplified with a 626 bp of the promoter sequence and 59 bp downstream to determine haplotypes. By PCR amplification, Dessinioti et al., 2011, described that single base extension (SBE) primers were designed to detect 15 SNPs from the MC1R gene: eight missense mutations (V60L, D84C, V92M, R142H, R151C, R160W, R165Q, D294H); two insertion mutations (179InsC, 291InsA); two silent mutations (P300P, T314T) and three important regulatory element, SP-1, in the MC1R promoter (rs3212359; rs3212360; rs3212361) (Le Pape et al., 2009). The 15 MC1R SNPs were carried out in a multiplexed SBE reaction using either Snapshot reaction chemistry or detection by capillary electrophoresis or biotin-ddNTPs with the monomeric avidin triethylamine purification (MATP) protocol and detection by MALDI-TOF MS. Sanchez, 2003 discovered that two highly polymorphic SNPs r359 or r361 may be useful to determine the haplotype using allele-specific PCR or allele-specific hybridization. He observed that a person with red hair develops R/R genotype; with blond or dark hair a wt/wt genotype and that of a RR/wt genotype developed a dark or blond and not red colored hair.

Different Pigment Produced by MC1R Gene and Their Function

Melanocyte pigments are mostly responsible for synthesizing of eumelanin, a relatively insoluble black or brown pigment or pheomelanin, a cysteine-rich red or yellow pigment that is soluble in dilute alkali (Mills, 2009). This phenomenon is often referred to as pigment-type switching and is regulated by the Agoutimelanocortin 1receptor (MC1R) pathway. MC1R is a G-protein coupled receptor expressed in melanocytes, whereas Agouti protein is a paracrine signalling molecule secreted by specialized dermal cells that inhibits MC1R signalling (April and Barsh, 2006; Cone, 1996). In laboratory mice, gain-of-functional mutations constitutively activate the MC1R (e.g. sombre, MC1Rso) cause exclusive production of eumelanin, whereas loss-of-function of MC1R mutations (e.g. recessive yellow, MC1Re) cause exclusive production of pheomelanin (Robbins, 1993). On the other hand, because Agouti is a MC1R antagonist, gain-of-function Agouti mutations (e.g. lethal yellow, Ay) cause exclusive production of pheomelanin, whereas loss of function mutations (e.g. extreme nonagouti, ae) cause exclusive production of eumelanin (Siracusa, 1994). Within the melanocyte, eumelanin and pheomelanin are synthesized in structurally distinct melanosomes. Eumelanin and pheomelanin are derived from a common precursor, dopaquinone, formed by oxidation of tyrosine by tyrosinase (Tyr). When MC1R activity is low, low tyrosinase activity and high cysteine levels result in pheomelanin production from dopaquinone. Slc7a11, which encodes for a melanocyte-specific cystine transporter, has been found to be required for pheomelanin synthesis (Chintala, 2005). During active MC1R signaling, low cysteine levels results in the multi-step conversion of dopaquinone to eumelanin and is catalysed in turn by dopachrome tautomerase (Dct) and tyrosinase-related protein 1 (Tyrp1) (Ito and Wakamatsu, 2008). Gene expression profiling experiments in which Dct and Tyrp1 were down regulated in skin of mice that carry loss of function mutations in the MC1R, which is consistent with previous reports that they are downstream targets of MC1R signalling (April and Barsh, 2006; Le Pape et al., 2009). Conversely, Slc7a11 was up regulated in the skin of mutant animals, which indicates that it is also regulated by the MC1R and supports model in which cystine transport plays an instructive role in pigment type switching.

Laboratory Animal Coat Colour Genetics

Mammalian skin contains only one pigment cell type the melanocyte which originates from the neural crest as unpigmented melanoblasts during embryonic day E8.5 in the mouse. The melanoblasts, which are precursors to melanocyte, first migrate along a dorsolateral pathway between the dermatome and ectoderm, before migrating through the dermis in a dorsal to ventral direction (Bennett, 2003). At approximately E12.5, melanoblasts move into the overlying epidermis and eventually into the developing hair follicles. In the mature hair follicle, melanoblasts will either differentiate between three melanocyte in the hair matrix or become melanocyte stem cells residing in the bulge region that will regenerate differentiated melanocyte during each hair cycle (Ringholm et al., 2004). In the mouse, genes that encode the receptor-ligand pair, Kit and Kitl, as well as Mitf, a transcription factor that regulates many melanocyte specific genes, are important for melanoblast development and survival, whereas genes that encode the receptor-ligand pair, Ednrb and Edn3, are responsible for proper migration of melanoblasts during development (Steingrímsson, 2006). During the active growth phase of the hair cycle, hair follicle melanocytes form functional units with neighbouring precordial keratinocyte postulated by Ringholm et al., 2004. In this process, pigment granules, called melanosomes are transferred from the dendritic ends of melanocyte to adjacent keratinocyte that will ultimately form the pigmented hair shaft (Slominski, 2005).

Feline Coat Colour Genetics

MC1R is responsible for regulating the hormone α-melanocyte stimulating hormone, (α-MSH), which is involved in pigment production (Barsh, 1996). MC1R has known effects on pigments in many animals. In jaguars, Panthera onca, and jaguarundis, Puma yagouaroundi, a dominant mutation of MC1R is responsible for melanism, the overproduction of eumelanin (Eizirik et al., 2003). However, melanism due to MC1R in domestic cats, Felis catus, follows a recessive inheritance pattern (Eizirik et al., 2003). By contrast, repression of MC1R can lead to lack of pigment, as in the case of the Kermode bear, Ursus americanus kermodei, which is a white color morph of the black bear (Ritland et al., 2001). The lack of eumelanin is caused by a recessive mutation at codon 298, replacing tyrosine with cytosine (Ritland et al., 2001). As with the case of the white tiger, the kermode bear is not an albino. 9 ASIP was also selected as a candidate gene due to antagonistic relationship to MC1R, silencing the effects of α-MSH (Rieder et al., 2001). Like MC1R, mutations in ASIP also affect some felid species. Leopards, Panthera pardus, and Asian golden cats, Pardofelis temminckii, appear melanistic due to single nucleotide polymorphism, (SNP), mutations in ASIP that cause ASIP to lose function (Schneider et al., 2012). In this case, a loss of function has led to melanistic individual. In contrast, a gain of function in ASIP could lead to an individual with reduced pigment production. The ASIP gene contains three coding exons, the first two of which were sequenced by former undergraduate research scholar Larkin, 2012.

Dog Coat Colour Genetics

A population-based association study in the domestic dog and implicated a novel gene the K locus—in pigment type 5 switching (Candille et al., 2007). K encodes for a beta-defensin (CBD103) that is highly expressed in dog skin and is structurally similar to Agouti. A dominantly inherited mutation in CBD103 is thought to cause constitutive production of eumelanin by competitively inhibiting the ability of Agouti to bind to the MC1R, and beta defensins represent a novel class of signaling peptides that can modulate MC1R signaling and contribute to mammalian coat colour variation (Anderson and Thompson, 2002).

Pig Coat Colour Genetics

Extension/MC1R is one of the major coat color loci in pigs. Ollivier and Sillver, 1978 has illustrated that a series of alleles with phenotypic effects has been established by segregation analyses of crossing breeding. Sequence analysis of five MC1R alleles corresponding to five different E alleles has revealed its mechanism of action (Kijas et al., 1998). Wild boars (E1/E1) possess wild-type alleles (MC1R*1 or *5) which needed for the expression of wild-type color. Large black and meishan pigs (ED1/ED1) carry MC1R*2, which contains a missense mutation L99P postulated to cause a constitutively active receptor revealed by Otto, 2007. Another black breed Hampshire (ED2/ED2), possesses MC1R*3 associated with the missense mutation D121N. The recessive red coat color of swine was studied in Duroc (e/e), found to be associated with MC1R*4 (Giuffra et al., 2000). This harbors two missense mutations, one of which (A240T) is a strong candidate to disrupt receptor function. The MC1R mutation could cause a red coat color with distinct black spots since mutations at this locus usually give uniform dominant black color or recessive red colour (Kijas et al., 2001). Two functionally significant MC1R mutations in the EP allele, a 2-bp insertion (nt67insCC) causing a frameshift unique to this allele and a missense mutation (D121N) which shared with the ED2 allele associated with dominant black color. The insertion clearly inactivates the MC1R gene function, thus expected to give a uniform red coat color as observed in the Tamworth and Hereford pigs (Kijas et al., 2001). However, the black spots on EP/EP homozygotes express transcripts in which the normal reading frame has been restored. The black color of these spots is due to the presence of the D121N substitution. The wild type E1 allele is dominant to EP, and E1/ EP heterozygotes from our Wild Boar intercross showed the wild-type color. However, a few black spots were generally observed in E1/EP heterozygotes but not in E1/E1 homozygotes. White pigs of the Large White and Landrace breeds do not show black spots because of epistatic interaction of the Dominant white/KIT alleles causing a defect in melanocyte migration (Marklund et al., 1998). Porter, 1993 reported that in the absence of Dominant white alleles, black spots are observed in some breeds (Pietrain, Linderd) but not in others (Tamworth, Hereford). Both the e and EP alleles in the Tamworth samples resulted in red coat color. The black spots in EP/EP pigs may occur on a red or white background.

Cattle Coat Colour Genetics

In cattle, differences in base colour are attributed to mutations in the MC1R gene, historically termed the extension locus, with alleles coding for black (ED), red (e), and wild-type (E+) were observed by Kerns et al., 2003. These alleles were presumed to follow a dominance model, in which ED > E+ > e. The wild-type allele (E+) produces a functional receptor that responds to both the α-melanocyte-stimulating hormone (α-MSH) ligand and its antagonist, agouti-signalling protein (ASP) was demonstrated by Royo, 2005. The ED allele, caused by a leucine to proline point mutation, creates a constitutively active receptor that results in eumelanin production most likely because of α-MSH ligand binding mimicry (Kerns et al., 2003). The recessive allele (e) leads to the production of only pheomelanin because of a frameshift mutation that creates a prematurely terminated, non-functional receptor (Eizirik et al., 2003).

Human Body Coat Colour

The human melanocortin-1 receptor (MC1R) is an integral membrane G-protein-coupled receptor (GPCR) of skin and hair follicle melanocytes (Ringholm et al., 2004). GPCRcs communicate the cells with their environment and upon receiving external stimuli trigger an adaptive response (Williams et al., 2011). In this regard, the binding of a small peptide, the a-melanocyte-stimulating hormone (a-MSH) to MC1R is coupled to a cAMP signaling pathway that stimulates eumelanogenesis (synthesis of brown/black melanins) (Schioth et al., 2005). In the absence of MC1R signaling, pheomelanogenesis (synthesis of yellow/red melanins) is the default pathway (Ito, 2003). Therefore, MC1R is a regulator of the amount and type of pigment production, and has thus been referred to as a major determinant of skin phototype (Garcia-Borron et al., 2005). In this regard, some nonfunctional MC1Rvariants lead to phenotypes characterized by red hair, fair skin, freckles, and poor tanning ability (the red hair and fair skin phenotype, RHC) in a dominant manner. These have been called R alleles, and include D84E, R151C, R160W, and D294H. Variants that do not lead to a total loss of function and that have weak or no association to the RHC phenotype (NRHC phenotype) are called r alleles, and include, for instance, V60L, V92M, and R163Q (Duffy et al., 2004; Beaumont et al., 2007; Dessinioti et al., 2011). As skin phototype is a risk factor for melanoma (Abdel-Malek and Ito, 2013), considerable effort has been dedicated to find association between variants at MC1R (Davies et al., 2012; Raimondi et al., 2008; Scherer et al., 2009; Williams et al., 2011). Less effort has been dedicated to understand pigmentation and melanoma risk from an evolutionary perspective. Interestingly, MC1R is highly diverse in humans: a recent literature review cataloged up to 57 non-synonymous and 25 synonymous variants in approximately 1 kb of coding DNA (Gerstenblith et al., 2007).

Harmful Effect of MC1R Gene on Animal Health

The MC1R protein contain 317 amino acid and a single stop codon encoded codon in a single exon and developed number of polymorphism that have been described in different human population (Duffy et al., 2004). In numerous experimental studies it had been revealed that human MC1R variants have been associated with variation in hair and skin pigmentation, increasing the risk of melanoma and other skin cancer (Otto et al., 2007). It was important to determine the SNPs that affect the phenotypes would make it possible to identify the molecular mechanism of diseases and phenotypic variation. Different tools have been developed to differentiate the deleterious or disease-associated SNPs occurring in a gene from the neutral or tolerated alteration (Eves and Haycock, 2010). Chagnon et al., 1997 used 11 different prediction tools to evaluate 92 nsSNPs in the MC1R gene in relation to their damaging or pathogenic effects and to predict the disease associated variance. By the combined result of 11 prediction tools 21 Ritland, 2001 predicted that a total of 57 nsSNPs (about 62%) were damaging by more than five tools. Two nsSNPs (T19I and I98V) showed neutral results in all tools. Fourteen nsSNPs (L48P, R67W, H70Y, P72L, S83P, R151H, S172I, L206P, T242I, G255R, P256S, C273Y, C289R and R306H) present damage results in all the prediction methods, likely a harmful variation in the gene. Wide varieties of neoplastic proliferations of a benign or malignant nature have been reported in felids (Montali, 1980). These have been observed in the integumentary-mammary, endocrine, reproductive, hematopoietic-lymphoreticular, digestive and hepatobiliary systems in felines (Scherer et al., 2009). Tumors of the eyes and adnexal structures are important tumors in cats that are reported to impair the patient’s vision, quality of life and survival (Davies et al., 2012).

A comprehensive study of the prevalence of feline eyelid tumors, published in 1993 by the Veterinary Medical Data Program and the Purdue Comparative Oncology Program, listed squamous cell carcinomas (SCCs), squamous papillomas, unclassifified carcinomas, basal cell carcinomas, fibromas, fibrosarcomas, adenomas, cystadenomas, adenocarcinomas (ACAs), lymphomas, histocytomas, mast cell tumors (MCTs), hemangiomas, hemangiosarcomas (HSAs), melanomas, neurofibromas and trichoepitheliomas (Miller et al., 2009). Cutaneous malignant epithelial tumors are reported as the most common neoplasm in felids (Davies et al., 2012) of which SCCs are predominant tumors that result from neoplastic proliferation of squamous stratified epithelium (Scherer et al., 2009).

SCCs of the eyelid is a common domestic feline adnexal tumor that is a malignant, locally invasive tumor originating in the epidermis (Caligiuri et al., 1988) and mostly affects white and older cats. These are characterized by a papillary or a cauliflower appearance having broad base and are usually seen in white cats with non-pigmented eyelids. Development of SCCs has been attributed to insult to the keratinocyte that may result from repeated exposure to UV radiation in susceptible animals (Caligiuri et al., 1988). Solar radiation may predispose the skin to SCC by damaging it, thus resulting in a preinvasive actinic precursor lesion, capable of malignant transformation (Scherer et al., 2009).


An extensive polymorphism of the MC1R gene exists in livestock animal, wild mammals and humans. In the present world scenario, skin or body coat colour is a variable trait in wild animal ethnic groups, as well as in domestic animal breeds. Thus, further studies on MC1R gene polymorphism in domestic animals demonstrating a unique coat colour should be continued. Comparative studies on the polymorphism of this gene will include breeds predisposed to adiposity. It would be worth to study MC1R variants that stratifying the hair color and body coat type to identify the specific contribution of each variant in melanoma development due to pigmentary and non pigmentary pathways. A possible role in melanoma development through non pigmentary pathways was demonstrated for p.I155T and p.R163H variants. The polymorphisms of the MC1R gene in some cattle breeds add new genetic information on the population structure at this locus for several other breeds. This information is useful to implement a breed traceability strategy for some livestock animal.


  1. Abdel-Malek, Z.A. and Ito, S. 2013. Being in the red: a no-win situation with melanoma. Pigment Cell Melanoma Res. 26: 164–166.
  2. Anderson, E.C. and Thompson, E.A. 2002. A model-based method for identifying species hybrids using multilocus genetic data. Genetics. 160: 1217–1229.
  3. April, C.S. and Barsh, G.S. 2006. Skin layer-specific transcriptional profiles in normal and recessive yellow (MC1Re/MC1Re) mice. Pigment Cell Research. 19: 194-205.
  4. Barsh, G.S. 1996. The genetics of pigmentation: from fancy genes to complex traits. Trends in Genetics. 46: 169-175.
  5. Beaumont, K.A, Shekar, S.L., Newton, R.A., James, M.R., Stow, J.L., Duffy, D.L. and Sturm, R.A. 2007. Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles. Hum Mol Genet. 16: 2249–2260.
  6. Bennett, D.C. and Lamoreux, M.L. 2003. The color loci of mice – a genetic century. Pigment Cell Res. 16: 333-344.
  7. Caligiuri, R.M., Carrier, E.R. and Jacobson, C.D. 1988. Corneal squamous cell carcinoma in a cheetah (Acinonyx jubatus). Journal of Zoo Animals and Medicine. 19: 219-222.
  8. Candille, S.I., Kaelin, C.B., Cattanach, B.M., Yu, B., Thompson, D.A., Nix, M.A., Kerns, J.A., Schmutz, S.M., Millhauser, G.L. and Barsh, G.S. 2007. A -defensin mutation causes black coat color in domestic dogs. Science. 318: 1418-1423.
  9. Chagnon, Y.C., Chen, W.J., Pérusse, L., Chagnon, M., Nadeau, A., Wilkison, W.O. and Bouchard, C. 1997. Linkage and association studies between the melanocortin receptors 4 and 5 genes and obesity-related phenotypes in the Québec Family Study. Mol Med. 3: 663–673.
  10. Chintala, S., Li, W., Lamoreux, M.L., Ito, S., Wakamatsu, K., Sviderskaya, E.V., Bennett, D.C., Park, Y.M., Gahl, W.A. and Huizing, M. 2005. Slc7a11 gene controls production of pheomelanin pigment and proliferation of cultured cells. Processed National Academic Science. 102: 10964-10969.
  11. Cone, R.D., Lu, D., Koppula, S., Vage, D.I., Klungland, H., Boston, B., Chen, W., Orth, D.N., Pouton, C. and Kesterson, R.A. 1996. The melanocortin receptors, agonists, antagonists, and the hormonal control of pigmentation. Recent Progress in Hormone Research. 51: 287-317.
  12. Davies, J.R., Randerson-Moor, J., Kukalizch, K., et al. (29 co-authors). 2012. Inherited variants in the MC1R gene and survival from cutaneous melanoma: a BioGenoMEL study. Pigment Cell Melanoma Res. 25: 384–394.
  13. Dessinioti, C., Antoniou, C., Katsambas, A. and Stratigos, A.J. 2011. Melanocortin 1 receptor variants: functional role and pigmentary associations. Photochem Photobiol 87(5): 978–987.
  14. Duffy, D.L., Box, N.F., Chen, W., Palmer, J.S., Montgomery, G.W., James, M.R., Hayward, N.K., Martin, N.G. and Sturm, R.A. 2004. Interactive effects of MC1R and OCA2 on melanoma risk phenotypes. Hum Mol Genet. 13: 447–461.
  15. Eizirik, E., Yuhki, N., Johnson, W., Menotti-Raymond, M., Hannah, S. and O’Brien, S. 2003. Molecular Genetics and Evolution of Melanism in the Cat Family. Current Biology. 13: 448-453.
  16. Everts, R.E., Rothuizen, J. and VanOost, B.A. 2000. Identification of a premature stop codon in the melanocyte-stimulating hormone receptor gene (MC1R) in Labrador and Golden retrievers with yellow coat colour. Anim Genet. 31(3): 194–199.
  17. Eves, P.C. and Haycock, J.W. 2010. Melanocortin signaling mechanisms. Adv Exp Med Biol. 681: 19–28.
  18. Garcia-Borron, J.C., Sanchez-Laorden, B.L. and Jimenez-Cervantes, C. 2005. Melanocortin-1 receptor structure and functional regulation. Pigment Cell Res. 18: 393–410.
  19. Gerstenblith, M.R., Goldstein, A.M., Fargnoli, M.C., Persi, K. and Landi, M.T. 2007. Comprehensive evaluation of allele frequency differences of MC1R variants across populations. Hum Mutat. 28: 495–505.
  20. Giuffra, E., Kijas, J.M.H., Amarger, V., Carlborg, O., Jeon, J.T. et al. 2000. The origin of the domestic pig: independent domestication and subsequent introgression. Genetics154:1785 1791.
  21. Goureau, A., Yerle, M., Schmitz, A., Riquet, J., Milan, D., Pinton, P., Frelat, G. and Gellin, J. 1996. Human and porcine correspondence of chromosome segments using bidirectional chromosome painting. Genomics. 36(2): 252–262.
  22. Honan, P. 2008. Notes on the biology, captive management and conservation status of the Lord Howe Island Stick Insect (Dryococelus australis). Journal of Insect Conservation. 12(3): 399-413.
  23. Hulsman, H.L.L., Sanders, O.J., Riley, G.D., Abbey, A.C. and Gill, A.C. 2014. Identification of a major locus interacting with MC1R and modifying black coat color in an F2 Nellore-Angus population. Genetics Selection Evolution. 46: 4-9.
  24. Ito, S. and Wakamatsu, K. 2008. Chemistry of mixed melanogenesis-pivotal roles of dopaquinone. Photochemical Photobiology. 84: 582-592.
  25. Ito, S. 2003. A chemist’s view of melanogenesis. Pigment Cell Res. 16: 230–236.
  26. Kerns, J.A., Olivier, M., Lust, G. and Barsh, G.S. 2003. Exclusion of melanocortin-1 receptor (MC1R) and Agouti as candidates for dominant black in dogs. Journal of Heredity.94: 75-79.
  27. Kijas, J.M.H., Moller, M., Plastow, G. and Andersson, L. 2001. A frameshift mutation in MC1R and a high frequency of somatic reversions cause black spotting in pigs. Genetics. 158: 779–785.
  28. Kijas, J.M.H., Wales, R., Tornsten, A., Chardon, P., Moller, M. et al., 1998. Melanocortin receptor 1 (MC1R) mutations and coat color in pigs. Genetics. 150: 1177–1185.
  29. Larkin, E.A. 2012. Investigation of genes associated with the white coat color in tigers. (Undergraduate Research Thesis). Texas A&M University, College Station, Texas.
  30. Le Pape, P.T., Giubellino, A., Valencia, J.C., Wolber, R. and Hearing, V. 2009. Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the MC1R. Process National Academic Science. 106: 1802-1807.
  31. Lin, C.J. and Tam, R.C. 2001. Transcriptional regulation of CD28 expression by CD28GR, a novel promoter element located in exon 1 of the CD28 gene. The Journal of Immunology. 166: 6134-6143.
  32. Loos, R.J. 2011. The genetic epidemiology of melanocortin 4 receptor variants. Eur J Pharmacol. 660: 156–164.
  33. MacDougall-Shackleton, E.A., Blanchard, L. and Gibbs, H.L. 2003. Unmelanized plumage patterns in old world leaf warblers do not correspond to sequence variation at the Melanocortin-1 receptor locus (MC1R). Molecular Biology and Evolution. 20: 1675-1681.
  34. Marklund, L., Moller, M.J., Sandberg, K. and Andersson, L. 1996. A missense mutation in the gene for melanocyte-stimulating hormone receptor (MC1R) is associated with the chestnut coat color in horses. Mammalian Genome. 7(12): 895-899.
  35. Marklund, S., Kijas, J., Rodriguez-Martinez, H., Ronnstrand, L., Funa, K. et al., 1998. Molecular basis for the dominant white phenotype in the domestic pig. Genome Res. 8: 826–833.
  36. Miller, C.L., Murakami, P., Ruczinski, I., Ross, R.G., Sinkus, M., Sullivan, B. and Leonard, S. 2009. Two complex genotypes relevant to the kynurenine pathway and melanotropin function show association with schizophrenia and bipolar disorder. Schizophr Res. 113: 259-267.
  37. Mills, M.G. and Larissa, B. 2009. Not just black and white: pigment pattern development and evolution in vertebrates. Seminars in cell and Developmental Biology. 20: 72-81.
  38. Montali, R.J. 1980. An overview of tumors in zoo animals. In: The Comparative Pathology of Zoo Animals. Edition Montali RJ, Migaki G., Smithsonian Institution Press, Washington, DC. 531-542.
  39. Moro, O., Ideta, R. and Ifuku, O. 1999. Characterization of the promoter region of the human melanocortin-1 receptor (MC1R) gene. Biochem Biophys Res Commun. 262: 452-460.
  40. Mundy, N.I. and Kelly, J. 2003. Evolution of a pigmentation gene, the melanocortin-1 receptor, in primates. Am J Phys Anthropol. 121: 67–80.
  41. Nachman, M.W., Hoekstra, H.E. and D’Agostino, S.L. 2003. The genetic basis of adaptive melanism in pocket mice. Process of National Academic Science. 100: 5268-5273.
  42. Newton, J.M., Wilkie, A.L., He, L., Jordan, S.A., Metallinos, D.L., Holmes, N.G., Jackson, I.J. and Barsh, G.S. 2000. Melanocortin 1 receptor variation in the domestic dog. Mammalian Genome. 11(1): 24-30
  43. Ollivier, L. and Sellier, P. 1982. Pig genetics: a review. Ann Genet Sel anim. 14: 481–544.
  44. Otto, G., Roehe R, Looft, H., Thoelking, L., Knap, P.W., Rothschild, M.F., Plastow, G.S. and Kalm, E. 2007. Associations of DNA markers with meat quality traits in pigs with emphasis on drip loss. Meat Sci. 75: 185-195.
  45. Porter, V. 1993. Pigs: A Handbook to the Breeds of the World. Helm Information Ltd., Mountfield, East Sussex, United Kingdom.
  46. Raimondi, S., Sera, F., Gandini, S., Iodice, S., Caini, S.M. and Fargnoli, M.C. 2008. MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Int J Cancer. 122: 1753-1760
  47. Rieder, S., Taourit, S., Mariat, D., Langlois, B. and Guerin, G. 2001. Mutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotype in horse (Equus cabaluus). Mammalian Genome. 12: 450-455.
  48. Ringholm, A., Klovins, J., Rudzish, R., Phillips, S., Rees, J.L. and Schioth, H.B. 2004. Pharmacological characterization of loss of function mutations of the human melanocortin 1 receptor that are associated with red hair. J Invest Dermatol. 123: 917-923.
  49. Ritland, K., Newton, C. and Marshall, H.D. 2001. Inheritance and population structure of the white-phased ‘‘Kermode’’ black bear. Current Biology. 11: 1468-1472.
  50. Robbins, L.S., Nadeau, J.H., Johnson, K.R., Kelly, M.A., Roselli, R.L., Baack, E., Mountjoy, K.G. and Cone, R.D. 1993. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell. 72: 827-834.
  51. Rouzaud, F., Annereau, J.P., Valencia, J.C., Costin, G.E. and Hearing, V.J. 2003. Regulation of melanocortin 1 receptor expression at the mRNA and protein levels by its natural agonist and antagonist. FASEB J. 17: 2154-2156.
  52. Royo, L.J., Alvarez, I., Fernandez, I., Arranz, J.J., Gomez, E. and Goyache, F.J. 2005. The coding sequence of the ASIP gene is identical in nine wild type coloured cattle breeds. J Anim reed Genet. 122: 357-360.
  53. Sanchez, J.J. et al. 2003. Multiplex PCR and minisequencing of SNPs-a model with 35 Y chromosomes SNPs. Forensic Sci Int. 137: 74-84.
  54. Scherer, D., Nagore, E., Bermejo, J.L., Figl, A., Botella-Estrada, R., Thirumaran, R.K., Angelini, S., Hemminki, K., Schadendorf, D. and Kumar, R. 2009. Melanocortin receptor 1 variants and melanoma risk: a study of 2 European populations. Int J Cancer. 125: 1868-1875.
  55. Schioth, H.B., Haitina, T., Ling, M.K., Ringholm, A., Fredriksson, R., Cerda-Reverter, J.M. and Klovins, J. 2005. Evolutionary conservation of the structural, pharmacological, and genomic characteristics of the melanocortin receptor subtypes. Peptides. 26: 1886-1900.
  56. Schmutz, S.M. and Melekhovets, Y. 2012. Coat color DNA testing in dogs: theory meets practice. Mol Cell Probes. 26(6): 238-242.
  57. Schneider, A., David, V.A., Johnson, W.E., O’Brien, S.J., Barsh, G.S., Menotti-Raymond, M. and Eizirik, E. 2012. How the Leopard Hides Its Spots: ASIP Mutations and Melanism in Wild Cats. PloS one. 7-e50386.
  58. Siracusa, L.D. 1994. The agouti gene: turned on to yellow. Trends Genet. 10: 423-428.
  59. Slominski, A., Wortsman, J., Plonka, P.M., Schallreuter, K.U., Paus, R. and Tobin, D.J. 2005. Hair follicle pigmentation. J Invest Dermatol. 124: 13-21.
  60. Stefania, M., Barbara, P., Mauro, P., Pier, G.N. and Donato, C. 2008. Identification of the minimal melanocyte-specific promoter in the melanocortin receptor 1 gene. Journal of Experimental and Clinical Cancer Research. 27: 71-80.
  61. Steingrímsson, E., Copeland, N.G. and Jenkins, N.A. 2006. Mouse coat color mutations: from fancy mice to functional genomics. Dev Dyn. 235: 2401-2411.
  62. Sturm, R.A. et al. 2003. The role of melanocortin-1 receptor polymorphism in skin cancer risk phenotypes. Pigment Cell Res. 16: 266-272.
  63. Takeuchi, S., Suzuki, H., Yabuuchi, M. and Takahashi, S. 1997. A possible involvement of melanocortin 1-receptor in regulating. Current Biology. 13: 426-432.
  64. Tarnow, P., Schoneberg, T., Krude, H., Gruters, A. and Biebermann, H. 2003. Mutationally induced disulfide bond formation within the third extracellular loop causes melanocortin 4 receptor inactivation in patients with obesity. J Biol Chem. 278: 48666-48673.
  65. Theron, E., Hawkins, K., Bermingham, E., Ricklefs, R.E. and Mundy, N.I. 2001. The molecular basis of an avian plumage polymorphism in the wild: a melanocortin-1-receptor point mutation is perfectly associated with the melanic plumage morph of the bananaquit, Coereba flaveola. Current Biology. 11: 550-557.
  66. Vage, D.I., Lu, D., Klungland, H., Lien, S., Adalsteinsson, S. and Cone, R.D. 1997. Anon-epistatic interaction of agouti and extension in the fox, (Vulpes vulpes). National Genetics.15(3): 311-315.
  67. Webb, T.R., Chan, L., Cooray, S.N., Cheetham, M.E., Chapple, J.P. and Clark, A.J. 2009. Distinct melanocortin 2 receptor accessory protein domains are required for melanocortin 2 receptor interaction and promotion of receptor trafficking. Endocrinology. 150(2): 720-726.
  68. Williams, P.F., Olsen, C.M., Hayward, N.K. and Whiteman, D.C. 2011. Melanocortin 1 receptor and risk of cutaneous melanoma: a meta-analysis and estimates of population burden. Int J Cancer. 129: 1730-1740.
  69. Wynes, M.W. and Riches, D.W. 2005. Transcription of macrophage IGF-I exon 1 is positively regulated by the 5′-untranslated region and negatively regulated by the 5′-flanking region. Am J Physiol Lung Cell Mol Physiol. 288: 1089-1098.
  70. Yang, Y. 2011. Structure, function and regulation of the melanocortin receptors. Eur J Pharmacol. 660: 125-130.
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