Hair heterochromia may be caused by different mechanisms. At clinical work, we found a Chinese boy whose hair colour gradually turned to red. We record the diagnosis and treatment process and follow-up situation, finally find that altered hair colour phenotype is due to MC1R genetic mutations, rather than zinc deficiency. This rarely red hair colour phenotype improve our understanding of hair heterochromia caused by genetic mutations.

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In the last decades, researchers have been able to determine the molecular basis of some phenotypes, to test for evidence of natural selection upon them, and to demonstrate that the same genes or genetic pathways can be associated with convergent traits. Colour traits are often subject to natural selection because even small changes in these traits can have a large effect on fitness via camouflage, sexual selection or other mechanisms. The melanocortin-1 receptor locus (MC1R) is frequently associated with intraspecific coat colour variation in vertebrates, but it has been far harder to demonstrate that this locus is involved in adaptive interspecific colour differences. Here, we investigate the contribution of the MC1R gene to the colour diversity found in toucans (Ramphastidae). We found divergent selection on MC1R in the clade represented by the genus Ramphastos and that this coincided with the evolution of darker plumage in members of this genus. Using phylogenetically corrected correlations, we show significant and specific relationships between the rate of nonsynonymous change in MC1R (dN) and plumage darkness across Ramphastidae, and also between the rate of functionally significant amino acid changes in MC1R and plumage darkness. Furthermore, three of the seven amino acid changes in MC1R that occurred in the ancestral Ramphastos branch are associated with melanism in other birds. Taken together, our results suggest that the dark colour of Ramphastos toucans was related to nonsynonymous substitutions in MC1R that may have been subject to positive selection or to a relaxation of selective pressure. These results also demonstrate a quantitative relationship between gene and phenotype evolution, representing an example of how MC1R molecular evolution may affect macroevolution of plumage phenotypes.

Melanocortin 1 receptor (MC1R) gene variants are a major contributor to pigmentation characteristics and the modulation of sporadic basal cell carcinoma (BCC) risk. This is a hospital-based, case-control study to investigate the association of MC1R variants and pigmentary characteristics with the risk of BCC development in a Southern European population in Greece. In total, 141 patients with BCC and 166 controls were studied. Increased BCC risk was found for the presence of 2 or more MC1R variants (OR:3.07, 95% CI:1.13-8.34), or 2 or more variants of which at least 1 was major function (OR:7.15, 95% CI:1.37-5.52), after adjustment for the \'red hair colour\' (RHC) phenotype. Increased BCC risk persisted in the presence of 2 or more MC1R variants (OR:4.15, 95% CI:1.35-12.72), after adjustment for potential confounding factors including skin color (P:0.237) and atypical nevi (OR:9.57, 95% CI:2.19-41.81, P:0.003). MC1R genotype is a risk factor for the development of BCC in Greek patients independently of pigmentary characteristics, and the combination of MC1R variants may modulate this risk.

BACKGROUND: The MC1R gene implicated in melanogenesis and skin pigmentation is highly polymorphic. Several alleles are associated with red hair and fair skin phenotypes and contribute to melanoma risk.
OBJECTIVE: This work aims to assess the effect of different classes of MC1R variants, notably rare variants, on melanoma risk. Methods. MC1R coding region was sequenced in 1131 melanoma patients and 869 healthy controls. MC1R variants were classified as RHC (R) and non-RHC (r). Rare variants (frequency < 1%) were subdivided into two subgroups, predicted to be damaging (D) or not (nD).
RESULTS: Both R and r alleles were associated with melanoma (OR = 2.66 [2.20-3.23] and 1.51 [1.32-1.73]) and had similar population attributable risks (15.8% and 16.6%). We also identified 69 rare variants, of which 25 were novel. D variants were strongly associated with melanoma (OR = 2.38 [1.38-4.15]) and clustered in the same MC1R domains as R alleles (intracellular 2, transmembrane 2 and 7).
CONCLUSIONS: This work confirms the role of R and r alleles in melanoma risk in the French population and proposes a novel class of rare D variants as important melanoma risk factors. These findings may improve the definition of high-risk subjects that could be targeted for melanoma prevention and screening.

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BACKGROUND: Melanocortin-1 receptor (MC1R) gene variants are very common and are associated with melanoma risk, but their contribution to melanoma risk prediction compared with traditional risk factors is unknown. We aimed to 1) evaluate the separate and incremental contribution of MC1R genotype to prediction of early-onset melanoma, and compare this with the contributions of physician-measured and self-reported traditional risk factors, and 2) develop risk prediction models that include MC1R, and externally validate these models using an independent dataset from a genetically similar melanoma population.
METHODS: Using data from an Australian population-based, case-control-family study, we included 413 case and 263 control participants with sequenced MC1R genotype, clinical skin examination and detailed questionnaire. We used unconditional logistic regression to estimate predicted probabilities of melanoma. Results were externally validated using data from a similar study in England.
RESULTS: When added to a base multivariate model containing only demographic factors, MC1R genotype improved the area under the receiver operating characteristic curve (AUC) by 6% (from 0.67 to 0.73; P < 0.001) and improved the quartile classification by a net 26% of participants. In a more extensive multivariate model, the factors that contributed significantly to the AUC were MC1R genotype, number of nevi and previous non-melanoma skin cancer; the AUC was 0.78 (95% CI 0.75-0.82) for the model with self-reported nevi and 0.83 (95% CI 0.80-0.86) for the model with physician-counted nevi. Factors that did not further contribute were sun and sunbed exposure and pigmentation characteristics. Adding MC1R to a model containing pigmentation characteristics and other self-reported risk factors increased the AUC by 2.1% (P = 0.01) and improved the quartile classification by a net 10% (95% CI 1-18%, P = 0.03).
CONCLUSIONS: Although MC1R genotype is strongly associated with skin and hair phenotype, it was a better predictor of early-onset melanoma than was pigmentation characteristics. Physician-measured nevi and previous non-melanoma skin cancer were also strong predictors. There might be modest benefit to measuring MC1R genotype for risk prediction even if information about traditional self-reported or clinically measured pigmentation characteristics and nevi is already available.

The Réunion grey white-eye (Zosterops borbonicus) is a single-island endemic passerine bird that exhibits striking geographically structured melanic polymorphism at a very small spatial scale. We investigated the genetic basis of this color polymorphism by testing whether the melanocortin-1 receptor (MC1R), a gene often involved in natural melanic polymorphism in birds, was associated with the observed plumage variation. Although we found three non-synonymous mutations, we detected no association between MC1R variants and color morphs, and the main amino-acid variant found in the Réunion grey white-eye was also present at high frequency in the Mauritius grey white-eye (Zosterops mauritianus), its sister species which shows no melanic polymorphism. In addition, neutrality tests and analysis of population structure did not reveal any obvious pattern of positive or balancing selection acting on MC1R. Altogether these results indicate that MC1R does not play a role in explaining the melanic variation observed in the Réunion grey white-eye. We propose that other genes such as POMC, Agouti or any other genes involved in pigment synthesis will need to be investigated in future studies if we are to understand how selection shapes complex patterns of melanin-based plumage pigmentation.
BACKGROUND: All sequences submitted to Genbank. Accession number: JX914505 to JX914564.

Through the use of PCR based coat color tests, we were able to diagnose a dog that exhibits an unusual coat color phenotype as an XX/XX chimera. Coat color alleles vary widely among dog breeds, presenting a novel method for detecting chimerism using diagnostic tests for known coat color alleles.

BACKGROUND: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated cortisol deficiency. Mutations in the gene encoding the ACTH receptor (MC2R) account for 25% of cases. One significant feature is generalized skin hyperpigmentation, which is thought to be due to elevated ACTH acting on the melanocortin 1 receptor (MC1R).
OBJECTIVE: The aim of the study was to determine the cause of a nonhyperpigmented case of FGD.
METHODS: The patient presented at 4 yr of age with hypoglycemia after prolonged fasting during a respiratory tract infection. She had further hypoglycemic attacks and was diagnosed with isolated glucocorticoid deficiency at 6 yr of age. Her parents were consanguineous, and she had two unaffected sisters. Her physical examination was normal, except that her height and weight were greater than the 97th centile for a sex- and age-matched reference population. Interestingly, she had no hyperpigmentation despite very high ACTH levels.
RESULTS: Nucleotide sequence analysis revealed homozygous mutations c.478C>T in MC1R and c.455C>A in MC2R leading to R160W and T152K changes in the amino acid sequences, respectively. The R160W MC1R change has previously been implicated in a red hair/pale skin phenotype, and MC2R -T152K is trafficking defective. Both parents and two unaffected sisters were heterozygous for the MC1R mutation; additionally, one unaffected sister was heterozygous for the MC2R mutation, and the other was wild-type.
CONCLUSIONS: We report an unusual case of FGD without hyperpigmentation due to coexistent MC1R/MC2R mutations. This case is important because it demonstrates for the first time that the assumption that the action of ACTH on MC1R causes skin hyperpigmentation is correct.