Melanocortin MC1 receptor in human genetics and model systems

Beaumont, Kimberley A.; Wong, Shu Shyan; Ainger, Stephen A.; Liu, Yan Yan; Patel, Mira; Millhauser, Glenn L.; Smith, Jennifer J.; Alewood, Paul F.; Leonard, J. Helen; Sturm, Richard A.

doi:10.1016/j.ejphar.2010.11.040

Cited by 40 publications

(48 citation statements)

References 57 publications

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“…Population-based studies in diverse ethnic groups have shown the MC1R gene to be highly polymorphic with around 200 allelic variants identified [26,27] , 9 common variants are recognised in populations with European ancestry [28] . In Caucasians, some of the MC1R variants known as R -alleles, with a combined frequency of 18%, have a strong association with red hair, fair skin, freckling as well as increased melanoma and non-melanoma skin cancer risk.…”

Section: Mc1r: α-Msh Receptor and The Gene For Red Hair Colourmentioning

confidence: 99%

“…Conversely, low tyrosinase activity and high availability of cysteine lead to the less photoprotective and potentially phototoxic pheomelanins [31] . The main determinant of the amount and type of pigments formed within epidermal melanocytes is the MC1R genotype status [26,28] .…”

Section: Mc1r: α-Msh Receptor and The Gene For Red Hair Colourmentioning

confidence: 99%

“…Protein kinase A (PKA) is then activated, followed by the phosphorylation of members of the cAMP responsive-element binding protein (CREB) family of transcription factors, and CREB-mediated activation of Microphthalmia transcription factor ( MITF ) gene expression. MITF is a key positive regulator of melanocyte differentiation markers including tyrosinase activity, increased protein levels of TYRP1 and dopachrome tautomerase (DCT), leading to the biosynthesis of eumelanin pigments [26,28] .…”

Section: Mc1r: α-Msh Receptor and The Gene For Red Hair Colourmentioning

confidence: 99%

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Skin Pigmentation Genetics for the Clinic

Ainger

Jagirdar²,

Lee³

et al. 2017

Dermatology

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Human pigmentation characteristics play an important role in the effects of sun exposure, skin cancer induction and disease outcomes. Several of the genes most important for this diversity are involved in the regulation and distribution of melanin pigmentation or enzymes involved in melanogenesis itself within the melanocyte cell present in the skin, hair and eyes. The single nucleotide polymorphisms and extended haplotypes within or surrounding these genes have been identified as risk factors for skin cancer, in particular, melanoma. These same polymorphisms have been under selective pressure leading towards lighter pigmentation in Europeans in the last 5,000-20,000 years that have driven the increase in frequency in modern populations. Although pigmentation is a polygenic trait, due to interactive and quantitative gene effects, strong phenotypic associations are readily apparent for these major genes. However, predictive value and utility are increased when considering gene polymorphism interactions. In melanoma, an increased penetrance is found in cases when pigmentation gene risk alleles such as MC1R variants are coincident with mutation of higher-risk melanoma genes including CDKN2A, CDK4 and MITF E318K, demonstrating an interface between the pathways for pigmentation, naevogenesis and melanoma. The clinical phenotypes associated with germline changes in pigmentation and naevogenic genes must be understood by clinicians, and will be of increasing relevance to dermatologists, as genomics is incorporated into the delivery of personalised medicine.

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Section: Mc1r: α-Msh Receptor and The Gene For Red Hair Colourmentioning

confidence: 99%

Section: Mc1r: α-Msh Receptor and The Gene For Red Hair Colourmentioning

confidence: 99%

Section: Mc1r: α-Msh Receptor and The Gene For Red Hair Colourmentioning

confidence: 99%

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Skin Pigmentation Genetics for the Clinic

Ainger

Jagirdar²,

Lee³

et al. 2017

Dermatology

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“…Because of low innate levels of eumelanin, fair-skinned individuals are much more prone to acute and chronic effects of UV radiation [16][17][18] . Skin pigmentation, melanoma risk and the ability to "tan" after UV exposure all correlate with the signaling ability of the melanocortin 1 receptor (Mc1r), a G s -coupled seven transmembrane surface receptor on melanocytes [19][20][21][22] . When Mc1r binds its cognate high-affinity ligand, α-melanocyte stimulating hormone (α-MSH), there is activation of adenylyl cyclase and production of the second messenger cAMP 23 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Induction of Epidermal Melanin and Protection Against Sunburn in a Humanized Mouse Model

Amaro-Ortiz

Vanover

Scott

et al. 2013

JoVE

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Fairness of skin, UV sensitivity and skin cancer risk all correlate with the physiologic function of the melanocortin 1 receptor, a G s -coupled signaling protein found on the surface of melanocytes. Mc1r stimulates adenylyl cyclase and cAMP production which, in turn, up-regulates melanocytic production of melanin in the skin. In order to study the mechanisms by which Mc1r signaling protects the skin against UV injury, this study relies on a mouse model with "humanized skin" based on epidermal expression of stem cell factor (Scf). K14-Scf transgenic mice retain melanocytes in the epidermis and therefore have the ability to deposit melanin in the epidermis. In this animal model, wild type Mc1r status results in robust deposition of black eumelanin pigment and a UV-protected phenotype. In contrast, K14-Scf animals with defective Mc1r signaling ability exhibit a red/blonde pigmentation, very little eumelanin in the skin and a UV-sensitive phenotype. Reasoning that eumelanin deposition might be enhanced by topical agents that mimic Mc1r signaling, we found that direct application of forskolin extract to the skin of Mc1r-defective fair-skinned mice resulted in robust eumelanin induction and UV protection 1 . Here we describe the method for preparing and applying a forskolin-containing natural root extract to K14-Scf fair-skinned mice and report a method for measuring UV sensitivity by determining minimal erythematous dose (MED). Using this animal model, it is possible to study how epidermal cAMP induction and melanization of the skin affect physiologic responses to UV exposure. Video LinkThe video component of this article can be found at

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“…Of the many developmentally and environmentally induced agonists of MC1R, the hormone αMSH, which is secreted in response to the exposure of keratinocytes to UV radiation, is of particular interest because it mediates the tanning response. Partial or complete loss-of-function mutations in MC1R are the primary cause of a suite of pigmentation traits-red hair, freckles, and unusually light skin that burns but does not tan-that is common in Scotland, Ireland, and, to a lesser degree, other areas of Northern Europe (8). Continental-scale differences in the pattern of variation at MC1R are striking.…”

Section: Local Adaptationmentioning

confidence: 99%

Human Genetic Individuality

Olson

2012

Annu. Rev. Genom. Hum. Genet.

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The central preoccupation of human genetics is an effort to understand the genotypic basis of human phenotypic diversity. Although recent progress in identifying the genes that, when mutated, underlie major genetic diseases has been rapid, knowledge of the genetic influences on the vast range of variable, and at least partially heritable, traits that constitute the "normal" range of human phenotypic variation lags. Spectacular advances in our knowledge of human genetic variation have laid the groundwork for a synthesis of insights from medical genetics, population genetics, molecular evolution, and the study of human origins that places basic constraints on models of human genetic individuality. Balancing selection, local adaptation, mutation-selection balance, and founder effects have all extensively shaped contemporary genetic variation. Long-term-balancing selection appears largely to reflect the consequences of host-pathogen arms races. Local adaptation has been widespread-and involved responses to a plethora of selective pressures, some identifiable but most unknown. However, it appears to be a combination of mutation-selection balance and founder effects that largely accounts for genetic individuality. If true, this inference has major implications for future research programs in human genetics.

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Melanocortin MC1 receptor in human genetics and model systems

Cited by 40 publications

References 57 publications

Skin Pigmentation Genetics for the Clinic

Skin Pigmentation Genetics for the Clinic

Pharmacologic Induction of Epidermal Melanin and Protection Against Sunburn in a Humanized Mouse Model

Human Genetic Individuality

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