Dersimelagon in Erythropoietic Protoporphyrias.

BACKGROUND: Erythropoietic protoporphyria and X-linked protoporphyria are inborn errors of heme biosynthesis that cause elevated circulating levels of metal-free protoporphyrin and phototoxicity. Both disorders are characterized by excruciating phototoxic attacks after exposure to visible light. Dersimelagon is a new, orally administered, selective melanocortin 1 receptor agonist that increases levels of skin eumelanin. METHODS: We conducted a randomized, placebo-controlled, phase 2 trial to investigate the efficacy and safety of dersimelagon with respect to the time to onset and the severity of symptoms associated with sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria. Patients 18 to 75 years of age were randomly assigned in a 1:1:1 ratio to receive placebo or dersimelagon at a dose of 100 or 300 mg once daily for 16 weeks. The primary end point was the change from baseline to week 16 in the time to the first prodromal symptom associated with sunlight exposure. Patients recorded daily sunlight exposure and symptom data in an electronic diary. Quality of life and safety were also assessed. RESULTS: Of the 102 patients (93 with erythropoietic protoporphyria and 9 with X-linked protoporphyria) who underwent randomization, 90% completed the treatment period. The mean daily time to the first prodromal symptom associated with sunlight exposure increased significantly with dersimelagon: the least-squares mean difference from placebo in the change from baseline to week 16 was 53.8 minutes in the 100-mg dersimelagon group (P = 0.008) and 62.5 minutes in the 300-mg dersimelagon group (P = 0.003). The results also suggest that quality of life improved in patients receiving dersimelagon as compared with placebo. The most common adverse events that occurred or worsened during treatment were nausea, freckles, headache, and skin hyperpigmentation. CONCLUSIONS: At both doses evaluated, dersimelagon significantly increased the duration of symptom-free sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria. (Funded by Mitsubishi Tanabe Pharma; Endeavor ClinicalTrials.gov number, NCT03520036.).

Selective sweeps on different pigmentation genes mediate convergent evolution of island melanism in two incipient bird species.

Insular organisms often evolve predictable phenotypes, like flightlessness, extreme body sizes, or increased melanin deposition. The evolutionary forces and molecular targets mediating these patterns remain mostly unknown. Here we study the Chestnut-bellied Monarch (Monarcha castaneiventris) from the Solomon Islands, a complex of closely related subspecies in the early stages of speciation. On the large island of Makira M. c. megarhynchus has a chestnut belly, whereas on the small satellite islands of Ugi, and Santa Ana and Santa Catalina (SA/SC) M. c. ugiensis is entirely iridescent blue-black (i.e., melanic). Melanism has likely evolved twice, as the Ugi and SA/SC populations were established independently. To investigate the genetic basis of melanism on each island we generated whole genome sequence data from all three populations. Non-synonymous mutations at the MC1R pigmentation gene are associated with melanism on SA/SC, while ASIP, an antagonistic ligand of MC1R, is associated with melanism on Ugi. Both genes show evidence of selective sweeps in traditional summary statistics and statistics derived from the ancestral recombination graph (ARG). Using the ARG in combination with machine learning, we inferred selection strength, timing of onset and allele frequency trajectories. MC1R shows evidence of a recent, strong, soft selective sweep. The region including ASIP shows more complex signatures; however, we find evidence for sweeps in mutations near ASIP, which are comparatively older than those on MC1R and have been under relatively strong selection. Overall, our study shows convergent melanism results from selective sweeps at independent molecular targets, evolving in taxa where coloration likely mediates reproductive isolation with the neighboring chestnut-bellied subspecies.

Defining novel causal SNPs and linked phenotypes at melanoma-associated loci.

A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher's exact test analyses identified 66 variants associated with melanoma risk. Sequential conditional logistic regression identified the distinct haplotypes on which variants reside, and massively parallel reporter assays provided biological insights into how these variants influence gene function. We performed further analyses to link variants to melanoma risk phenotypes and assessed their association with melanoma-specific survival. Our analyses replicate previously known associations in the melanocortin 1 receptor (MC1R) and tyrosinase (TYR) loci, while identifying novel potentially causal variants at the MTAP/CDKN2A and CASP8 loci. These results improve our understanding of the architecture of melanoma risk and outcome.

Canine coat color E locus updates: Identification of a new MC1R variant causing 'sable' coat color in English Cocker Spaniels and a proposed update to the E locus dominance hierarchy.

The coat color phenotype 'sable' occurs in the English Cocker Spaniel dog breed. It closely resembles other canine color patterns known as domino/grizzle/pied (eA allele) and grizzle/domino (eG allele) determined by variants in the melanocortin 1 receptor gene (MC1R; 'extension' or E locus), a key multi-allele regulator of coat color. We examined genetic variation in MC1R, and found one new non-synonymous variant, c.250G>A (p.(Asp84Asn)), consistently associated with the English Cocker Spaniel 'sable' phenotype. We propose calling this newly identified allele eH and further show that the eA , eH and eG (previously known as EG ) alleles associate with similar phenotypes in dogs impacting genotypes regulated by beta-defensin 103 gene (CBD103; K locus) and agouti signaling protein gene (ASIP; A locus) in the absence of the EM and E alleles. This suggests that all three alleles are putative reduced-function variants of the MC1R gene. We propose the revised and updated E locus dominance hierarchy to be EM > E > eA /eH /eG > e1-3 .

Anti-Melanogenic Effects of Takifugu flavidus Muscle Hydrolysate in B16F10 Melanoma Cells and Zebrafish.

Abnormal melanogenesis can lead to hyperpigmentation. Tyrosinase (TYR), a key rate-limiting enzyme in melanin production, is an important therapeutic target for these disorders. We investigated the TYR inhibitory activity of hydrolysates extracted from the muscle tissue of Takifugu flavidus (TFMH). We used computer-aided virtual screening to identify a novel peptide that potently inhibited melanin synthesis, simulated its binding mode to TYR, and evaluated functional efficacy in vitro and in vivo. TFMH inhibited the diphenolase activities of mTYR, reducing TYR substrate binding activity and effectively inhibiting melanin synthesis. TFMH indirectly reduced cAMP response element-binding protein phosphorylation in vitro by downregulating melanocortin 1 receptor expression, thereby inhibiting expression of the microphthalmia-associated transcription factor, further decreasing TYR, tyrosinase related protein 1, and dopachrome tautomerase expression and ultimately impeding melanin synthesis. In zebrafish, TFMH significantly reduced black spot formation. TFMH (200 µg/mL) decreased zebrafish TYR activity by 43% and melanin content by 52%. Molecular dynamics simulations over 100 ns revealed that the FGFRSP (T-6) peptide stably binds mushroom TYR via hydrogen bonds and ionic interactions. T-6 (400 µmol/L) reduced melanin content in B16F10 melanoma cells by 71% and TYR activity by 79%. In zebrafish, T-6 (200 µmol/L) inhibited melanin production by 64%. TFMH and T-6 exhibit good potential for the development of natural skin-whitening cosmetic products.

Cis-acting mutation affecting GJA5 transcription is underlying the Melanotic within-feather pigmentation pattern in chickens.

Melanotic (Ml) is a mutation in chickens that extends black (eumelanin) pigmentation in normally brown or red (pheomelanin) areas, thus affecting multiple within-feather patterns [J. W. Moore, J. R. Smyth Jr, J. Hered. 62, 215-219 (1971)]. In the present study, linkage mapping using a back-cross between Dark Cornish (Ml/Ml) and Partridge Plymouth Rock (ml+/ml+ ) chickens assigned Ml to an 820-kb region on chromosome 1. Identity-by-descent mapping, via whole-genome sequencing and diagnostic tests using a diverse set of chickens, refined the localization to the genomic region harboring GJA5 encoding gap-junction protein 5 (alias connexin 40) previously associated with pigmentation patterns in zebrafish. An insertion/deletion polymorphism located in the vicinity of the GJA5 promoter region was identified as the candidate causal mutation. Four different GJA5 transcripts were found to be expressed in feather follicles and at least two showed differential expression between genotypes. The results showed that Melanotic constitutes a cis-acting regulatory mutation affecting GJA5 expression. A recent study established the melanocortin-1 receptor (MC1R) locus and the interaction between the MC1R receptor and its antagonist agouti-signaling protein as the primary mechanism underlying variation in within-feather pigmentation patterns in chickens. The present study advances understanding the mechanisms underlying variation in plumage color in birds because it demonstrates that the activity of connexin 40/GJA5 can modulate the periodic pigmentation patterns within individual feathers.

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-ß-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.

Zinc deficiency or genetic mutations?-A case report of hair heterochromia in the context of MC1R genetic mutations.

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.

Negative Modulation of B Cell Activation by Melanocortin 1 Receptor Signaling Protects against Membranous Nephropathy.

SIGNIFICANCE STATEMENT: Emerging evidence suggests that melanocortin neuropeptides-specifically adrenocorticotropic hormone-offer a novel, steroidogenic-independent therapeutic modality for membranous nephropathy (MN). The molecular mechanism underlying this beneficial effect, however, remains largely elusive. To investigate whether melanocortins modulate humoral immunity, the authors induced passive Heymann nephritis, a model of human MN, in wild-type and melanocortin 1 receptor (MC1R) knockout rats and treated them with melanocortin agents. Additional rats received adoptive transfer of bone marrow-derived cells beforehand from wild-type or MC1R knockout rats. The findings indicate that MC1R signaling plays a key role in negative modulation of B-cell activation and thereby suppresses humoral immune responses in passive Heymann nephritis, and suggest that MC1R signaling might offer a novel B cell-targeted therapeutic strategy for MN. BACKGROUND: Emerging evidence suggests that the pituitary neuropeptide melanocortins-specifically, adrenocorticotropic hormone-offer a novel nonsteroidogenic therapeutic modality for membranous nephropathy (MN). However, the mechanism(s) of action remains elusive. METHODS: To investigate whether melanocortins modulate humoral immunity, we induced passive Heymann nephritis (PHN), a model of MN, in wild-type (WT) and melanocortin 1 receptor (MC1R) knockout (KO) rats. We treated the animals with melanocortin agents-repository corticotropin injection, the nonsteroidogenic pan-melanocortin receptor agonist [Nle 4 , DPhe 7 ]-α-melanocyte stimulating hormone, the selective MC1R agonist MS05, vehicle gel, or phosphate-buffered saline-and evaluated kidney function, histology, and molecular changes. Additional rats received adoptive transfer of syngeneic bone marrow-derived cells beforehand from WT or MC1R KO rats. RESULTS: KO of MC1R worsened PHN and this was associated with increased deposition of autologous immunoglobulin G (IgG) and complement C5b-9 in glomeruli and higher circulating levels of autologous IgG-evidence of a sensitized humoral immune response. Melanocortin therapy ameliorated PHN in WT rats, coinciding with reduced glomerular deposition of autologous IgG and C5b -9. The beneficial efficacy of melanocortins was blunted in KO rats but restored by adoptive transfer of syngeneic bone marrow-derived cells derived from WT rats. Mechanistically, MC1R was expressed in B lymphocytes and was negatively associated with B cell activation. MC1R agonism triggered the expression of microphthalmia-associated transcription factor in activated B cells in a cAMP-dependent mode and also repressed the expression of interferon regulatory factor 4 (a lymphoid transcription factor essential for B-cell development and maturation), resulting in suppressed plasma cell differentiation and IgG production. CONCLUSIONS: MC1R signaling negatively modulates B cell activation and suppresses humoral immune responses in PHN, suggesting that MC1R signaling might offer a novel therapeutic target for MN.

Targeting the Melanocortin 1 Receptor in Melanoma: Biological Activity of α-MSH-Peptide Conjugates.

Malignant melanoma is one of the most aggressive and resistant tumor types, with high metastatic properties. Because of the lack of suitable chemotherapeutic agents for treatment, the 5-year survival rate of melanoma patients with regional and distant metastases is lower than 10%. Targeted tumor therapy that provides several promising results might be a good option for the treatment of malignant melanomas. Our goal was to develop novel melanoma-specific peptide-drug conjugates for targeted tumor therapy. Melanocortin-1-receptor (MC1R) is a cell surface receptor responsible for melanogenesis and it is overexpressed on the surface of melanoma cells, providing a good target. Its native ligand, α-MSH (α-melanocyte-stimulating hormone) peptide, or its derivatives, might be potential homing devices for this purpose. Therefore, we prepared three α-MSH derivative-daunomycin (Dau) conjugates and their in vitro and in vivo antitumor activities were compared. Dau has an autofluorescence property; therefore, it is suitable for preparing conjugates for in vitro (e.g., cellular uptake) and in vivo experiments. Dau was attached to the peptides via a non-cleavable oxime linkage that was applied efficiently in our previous experiments, resulting in conjugates with high tumor growth inhibition activity. The results indicated that the most promising conjugate was the compound in which Dau was connected to the side chain of Lys (Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2). The highest cellular uptake by melanoma cells was demonstrated using the compound, with the highest tumor growth inhibition detected both on mouse (38.6% on B16) and human uveal melanoma (55% on OMC-1) cells. The effect of the compound was more pronounced than that of the free drug.

Hematopoietic-specific melanocortin 1 receptor signaling protects against nephrotoxic serum nephritis and mediates the beneficial effect of melanocortin therapy.

The melanocortin hormone system has emerged as a novel therapeutic target for treating refractory glomerular diseases. However, the role of hematopoietic melanocortin 1 receptor (MC1R) signaling remains unknown. Upon insult by rabbit nephrotoxic serum, MC1R null-mutant mice developed more severe crescentic glomerulonephritis than wild-type mice, marked by aggravated proteinuria, kidney dysfunction and histologic lesions. Melanocortin therapy, using Repository Corticotropin Injection (Acthar Gel), the pan-melanocortin receptor agonist NDP-MSH, or the MC1R agonist MS05, ameliorated experimental nephritis in wild-type mice but this effect was blunted in null mice. Exacerbated experimental nephritis in null mice was associated with increased glomerular deposition of autologous IgG and C5b-9, in parallel with higher circulating levels of autologous IgG2c and IgG3. Additionally, the Th1 immune response was potentiated in null mice with experimental nephritis, accompanied by diminished kidney FoxP3+ regulatory T cells. Kidney infiltration of macrophages was also augmented by MC1R deficiency with an enhanced M1 polarization. Moreover, adoptive transfer of syngeneic bone marrow-derived cells from wild-type mice mitigated experimental nephritis in null mice and restored the beneficial efficacy of melanocortins. Mechanistically, MC1R was expressed by diverse subsets of kidney leukocytes, including macrophages, T and B lymphocytes, and was inversely associated with the NFκB pathway, a key player in immune responses. MS05 attenuated the production of rabbit IgG-specific IgG2c and IgG3 in cultured wild-type splenocytes, and promoted M2 polarization in M1-primed wild-type macrophages, associated with NFκB inhibition. In contrast, in null splenocytes or macrophages, this effect of MS05 was barely detectable, but was mimicked by an NFκB inhibitor. Thus, hematopoietic MC1R signaling attenuates experimental nephritis and mediates the beneficial effect of melanocortin therapy via, in part, regulating the immune response.

Alpha-melanocyte stimulating hormone (α-MSH): biology, clinical relevance and implication in melanoma.

Alpha-melanocyte stimulating hormone (α-MSH) and its receptor, melanocortin 1 receptor (MC1R), have been proposed as potential target for anti-cancer strategies in melanoma research, due to their tissue specific expression and involvement in melanocyte homeostasis. However, their role in prevention and treatment of melanoma is still debated and controversial. Although a large body of evidence supports α-MSH in preventing melanoma development, some preclinical findings suggest that the α-MSH downstream signalling may promote immune escape and cancer resistance to therapy. Additionally, in metastatic melanoma both MC1R and α-MSH have been reported to be overexpressed at levels much higher than normal cells. Furthermore, targeted therapy (e.g. BRAF inhibition in BRAFV600E mutant tumours) has been shown to enhance this phenomenon. Collectively, these data suggest that targeting MC1R could serve as an approach in the treatment of metastatic melanoma. In this review, we explore the molecular biology of α-MSH with particular emphasis into its tumor-related properties, whilst elaborating the experimental evidence currently available regarding the interplay between α-MSH/MC1R axis, melanoma and antitumor strategies.

The Neuropeptide Alpha-Melanocyte-Stimulating Hormone Is Critical for Corneal Endothelial Cell Protection and Graft Survival after Transplantation.

Corneal transplantation is the most common form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain tissue transparency by pumping out excess water from the cornea. After transplantation, the rate of CEnC loss far exceeds that seen with normal aging, which can threaten sight. The underlying mechanisms are poorly understood. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide that is constitutively found in the aqueous humor with both cytoprotective and immunomodulatory effects. The curent study found high expression of melanocortin 1 receptor (MC1R), the receptor for α-MSH, on CEnCs. The effect of α-MSH/MC1R signaling on endothelial function and allograft survival in vitro and in vivo was investigated using MC1R signaling-deficient mice (Mc1re/e mice with a nonfunctional MC1R). Herein, the results indicate that in addition to its well-known immunomodulatory effect, α-MSH has cytoprotective effects on CEnCs after corneal transplantation, and the loss of MC1R signaling significantly decreases long-term graft survival in vivo. In conclusion, α-MSH/MC1R signaling is critical for CEnC function and graft survival after corneal transplantation.

Genetic fine-mapping reveals single nucleotide polymorphism mutations in the MC1R regulatory region associated with duck melanism.

Birds are among the most colourful terrestrial vertebrates, with various plumage colours and patterns. We conducted a genome-wide association study (GWAS) on an intercross F2 population of Pekin ducks and mallards (n = 722) and identified a 1.57-Mb genetic region (Chr11: 20,176,480-21,750,101 bp) related to duck melanism. Fine mapping by linkage disequilibrium (LD) and FST analysis narrowed the final candidate region to a region of 22,500 bp (Chr11: 20,677,500-20,700,000 bp) including three coding genes, TCF25, MC1R and TUBB3. Combined with transcriptome and qRT-PCR analysis, MC1R was identified as the unique genetic locus responsible for black plumage in ducks, and it was significantly more highly expressed in the feather bulbs of black ducks. We also identified 52G > A (Chr11: 20,696,354G > A) and 376G > A (Chr11: 20,696,678G > A) mutations in the MC1R coding region that have been widely studied in ducks. In addition, structural variations (SVs) were screened by nanopore sequencing, and no significant SV was found to be associated with the duck black plumage trait. However, we identified four novel single nucleotide polymorphisms in the MC1R regulator region (Chr11: 20,678,412G > A, Chr11: 20,679,236G > A, Chr11: 20,692,496 A > G and Chr11: 20,692,791 A > G) that had a strong association with the black plumage phenotype of ducks and combined with potential changes in transcription binding affinities. The luciferase reporter gene assay demonstrated that Chr11: 20,678,412G > A and Chr11: 20,679,236G > A led to significant promoter activity changes. Our research emphasizes the importance of MC1R regulatory region mutation in determining the duck black plumage phenotype, and these results expand our understanding of the genetic mechanism underlying duck plumage colour.

Melanocortin 1 receptor variants and their association with phenotypic characteristics and sporadic multiple primary melanomas in a cohort of 402 Spanish subjects.

The melanocortin 1 receptor (MC1R) gene is considered to be a major determinant of the risk of melanoma. The role of MC1R polymorphisms as predisposing factors for the development of a second primary melanoma is not well established. The present study analyses the characteristics from subjects with certain MC1R variants without any other genetic predisposition, as well as the risk of second primary melanoma associated with these variants. We performed a prospective longitudinal single-centre study based on follow-up information of 402 patients diagnosed with cutaneous melanoma. MC1R gene was sequenced in all subjects. High-risk variants were defined as those previously associated with melanoma (V60L, V92M, I155T, R160W, R163Q and D294H). 253 (63%) patients had at least one predisposing variant. These individuals had higher proportion of red/blonde hair, multiple primary melanomas and first melanoma diagnosis under the age of 60. Second primary melanomas were detected in 28 (3.8%) subjects. Having more than 25 melanocytic nevi was associated significantly to the development of second primary melanomas. A higher proportion of individuals carrying at least one predisposing MC1R variant develop a second melanoma, although statistical significance was not reached. Therefore, some MC1R polymorphisms might determine clinical and histological differences between patients with cutaneous melanoma and may represent a risk factor for second primary melanoma, although more studies are needed.

The MC1R r allele does not increase melanoma risk in MITF E318K carriers.

BACKGROUND: Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored. OBJECTIVES: To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K- individuals. MATERIALS AND METHODS: Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/- cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank). RESULTS: The cohort comprised 1165 MITF E318K- and 322 E318K+ individuals. In E318K- cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67-2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54-1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20-1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals. CONCLUSIONS: RHC alleles/genotypes modify melanoma risk differently in MITF E318K- and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K- individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals.

Palmitoylation-dependent activation of MC1R prevents melanomagenesis.

The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH) stimulates cAMP signalling and melanin production and enhances DNA repair after ultraviolet irradiation. Individuals carrying MC1R variants, especially those associated with red hair colour, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma. However, how MC1R activity is modulated by ultraviolet irradiation, why individuals with red hair are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit are unknown. Here we demonstrate a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is essential for activating MC1R signalling, 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-Mc1re/eJ mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, we show that pharmacological activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma.

High- and intermediate-risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium.

BACKGROUND: Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark-skinned individuals, are underrepresented. OBJECTIVES: We report a comprehensive pooled analysis of established high- and intermediate-penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium. METHODS: Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country. RESULTS: We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3-19.7), >3 affected members (OR 2.6; 95% CI 1.3-5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4-9.4) in the family (AUC 0.76, 95% CI 0.71-0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0-2.0 and OR 4.3; 95% CI 1.2-14.6, respectively). CONCLUSIONS: Variants in known high-penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment.

Polymorphisms in corticotrophin-releasing hormone-proopiomalanocortin (CRH-POMC) system genes: Neuroimmune contributions to psoriasis disease.

BACKGROUND: Skin is a target organ and source of the corticotropin-releasing hormone-proopiomelanocortin (CRH-POMC) system, operating as a coordinator and executor of responses to stress. Environmental stress exacerbates and triggers inflammatory skin diseases through modifying the cellular components of the immune system supporting the importance of CRH-POMC system in the pathogenesis of psoriasis. The aim of this study was to analyse the association of CRH-POMC polymorphisms with psoriasis and evaluate transcript expression of lesional psoriatic and normal skin in RNA-seq data. METHODS: Samples of 104 patients with psoriasis and 174 healthy controls were genotyped for 42 single nucleotide polymorphisms (SNPs) of CRH-POMC using Applied Biosystems SNPlex™ method. The transcript quantification was performed using Salmon software v1.3.0. RESULTS: This study demonstrated the associations between melanocortin 1 receptor (MC1R) polymorphisms rs2228479, rs3212369, dopachrome tautomerase (DCT) polymorphisms rs7987802, rs2031526, rs9524501 and psoriasis in the Tatar population. Very strong association was evident for the SNP rs7987802 in the DCT gene (pc = 5.95е-006) in psoriasis patients. Additionally, the haplotype analysis provided AT DCT (rs7992630 and rs7987802) and AGA MC1R (rs3212358, 2228479 and 885479) haplotypes significantly associated (pc ˂ 0.05) with psoriasis in the Tatar population, supporting the involvement of DCT and MC1R to the psoriasis susceptibility. Moreover, MC1R-203 and DCT-201 expression levels were decreased in psoriasis lesional skin compared with healthy control skin. CONCLUSIONS: This study is the first to identify genetic variants of the MC1R and DCT genes significantly associated with psoriasis in Tatar population. Our results support potential roles of CRH-POMC system genes and DCT in the pathogenesis of psoriasis.

MC1R Gene Variants and Their Relationship with Coat Color in South American Camelids.

In domestic camelids, fleece color is an essential characteristic because it defines the direction of production. Variants were determined in the MC1R gene that showed a relationship with coat color in alpacas and llamas at the level of the coding region. This report sequenced the MC1R gene from 290 alpacas (142 white, 84 black, 50 brown, and 14 light fawn), five brown llamas, nine vicuñas, and three guanacos to analyze the association between coat color and the MC1R gene among South American camelids. A total of nineteen polymorphisms were identified. Seven polymorphisms were significant; three of them were of nonsynonymous type (c.82A > G, c.376G > A, and c.901C > T), two were of synonymous type (c.126 T > C and c.933G > A), one was in the promoter region (-42C > G), and one was in the 3' UTR (+5T > C). More polymorphisms were found in domestic camelids than in wild camelids. Besides polymorphism, the association of polymorphisms might cause white and dark pigmentation in the fleece of South American camelids. In addition, the MC1R protein would answer the pigmentation in alpacas.