Melanocortin-4 Receptor Gene Research Articles

Prevalence and phenotypic characterization of MC4R variants in a large pediatric cohort.

We aimed to determine the prevalence of melanocortin-4 receptor (MC4R) variants in a large German cohort of children with obesity in a pediatric outpatient clinic and to ascertain whether there is a specific phenotype associated with loss-of-function variants as previously reported. Eight hundred and ninety-nine patients from our pediatric obesity clinic were screened for MC4R variants by DNA sequencing after PCR amplification. Retrospective statistical analysis of anthropometric and metabolic characteristics was performed, comparing patients with and without MC4R variants across the entire cohort (n=586) as well as in case-control analysis using patients with common sequence MC4R individually matched for age, sex and body mass index standard deviation score (SDS) (n=11 case-control pairs). We identified heterozygous variants within the coding region of the MC4R gene in n=22 (2.45%) patients. Fourteen (1.56%) had a variant that impaired receptor function. One new frameshift (p.F152Sfs), an yet unpublished nonsense mutation (p.Q156X) and one nonsynonymous variation (p.V65E) described in the Mouse Genome Database were detected. Across the whole cohort, at all ages, mean height SDS in subjects with impaired receptor function was higher than in patients with common sequence MC4R. In matched individuals, this trend persisted (8 of the 11 pairs) within the case-control setting. No differences were found regarding metabolic characteristics. The observed prevalence of mutations causing impaired receptor function in this large cohort is comparable to other pediatric cohorts. MC4R deficiency tends to lead to a taller stature, confirming previous clinical reports. The association of MC4R mutations with a distinct phenotype concerning metabolic characteristics remains questionable.

A Common Variant and the Transcript Levels of MC4R Gene Are Associated With Adiposity in Children: The IDEFICS Study.

The melanocortin-4 receptor gene (MC4R) plays a pivotal role in the regulation of body fat and food and energy intake. The objectives of the study were as follows: 1) to evaluate the association of variants rs17782313 and rs17700633 near the coding region of MC4R and 2) to evaluate the association of the transcript levels of MC4R with adiposity indices and percentage of energy from fat, carbohydrates, and protein in children. The Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants (IDEFICS) cohort was used, with examinations at baseline (T0) and after 2 years (T1). A total of 16 228 schoolchildren (2-9 y) from eight European countries participated in the study. A random sample of 4381 children genotyped for MC4R variants and a subsample of 410 children with MC4R expression data in peripheral blood cells (PBCs) were included in the analyses. Anthropometric measures and energy intake (total and from fat, carbohydrates, and protein) served as outcomes for adiposity status and for dietary behavior, respectively. At T0, the C allele of rs17782313 (minor frequency allele 23%) was significantly associated with higher values of adiposity indices (all P < .001). No association was found between rs17700633 (minor frequency allele 28%) and the variables under study. At T1, the C allele of rs17782313 was associated with a significantly higher increase in the adiposity indices over time (all P < .05). The MC4R expression levels in PBCs were inversely associated with body fat and energy intake from carbohydrates and directly with energy from fat (all P ≤ .05) but were not influenced by variants rs17782313 and rs17700633. The common variant rs17782313 near MC4R was cross-sectionally and longitudinally associated with body mass index and measures of body fatness in children aged 2-9 years. We showed, for the first time in humans, that MC4R expression levels in PBCs are related to body fat distribution and percentage of energy intake from carbohydrates and fat.

Fear of Pain Mediates the Association between MC1R Genotype and Dental Fear

Fear of pain is experienced in acute and chronic pain populations, as well as in the general population, and it affects numerous aspects of the orofacial pain experience, including pain intensity, pain-related disability, and pain behavior (e.g., avoidance). A related but separate construct—dental fear—is also experienced in the general population, and it influences dental treatment–seeking behavior and oral and systemic health. Minimal work has addressed the role of genetics in the etiologies of fear of pain and dental fear. Limited available data suggest that variants of the melanocortin 1 receptor (MC1R) gene may predict greater levels of dental fear. The MC1R gene also may be etiologically important for fear of pain. This study aimed to replicate the finding that MC1R variant status predicts dental fear and to determine, for the first time, whether MC1R variant status predicts fear of pain. Participants were 817 Caucasian participants (62.5% female; mean ± SD age: 34.7 ± 8.7 y) taking part in a cross-sectional project that identified determinants of oral diseases at the community, family, and individual levels. Participants were genotyped for single-nucleotide polymorphisms on MC1R and completed self-report measures of fear of pain and dental fear. Presence of MC1R variant alleles predicted higher levels of dental fear and fear of pain. Importantly, fear of pain mediated the relation between MC1R variant status and dental fear (B = 1.60, 95% confidence interval: 0.281 to 3.056). MC1R variants may influence orofacial pain perception and, in turn, predispose individuals to develop fears about pain. Such fears influence the pain experience and associated pain behaviors, as well as fears about dental treatment. This study provides support for genetic contributions to the development/maintenance of fear of pain and dental fear, and it offers directions for future research to identify potential targets for intervention in the treatment of fear of pain and dental fear.

Changes in body weight and fatness of sows during reproductive activity depending on LEPR and MC4R genes polymorphism

The use of genetic markers in selection of maternal breed gilts for reduced feed intake and fatness of pigs, may impact on their reproductive performance in subsequent breeding. The objective of the study was to analyse changes, over three consecutive lactations, in condition (body weight and fatness) and reproductive performance of Polish Large White (PLW) and Polish Landrace (PL) sows of known genotype at leptin receptor (LEPR) and melanocortin 4 receptor (MC4R) loci. The study involved 58 PLW and 65 PL gilts. Gilts and subsequently sows were monitored for body weight (BW) and backfat thickness (P2) over three reproductive cycles, and their litters were analysed for the number and body weight of the piglets. A total of 168 litters of PLW pigs and 186 litters of PL pigs were evaluated. It is concluded that over the three reproductive cycles, PLW sows exhibited higher weight gains and lower fatness compared to PL sows. The interaction between LEPR and MC4R genes had a significant effect on changes in body weight of the gilts, subsequently on changes in the condition of sows (BW and P2) during consecutive reproductive cycles, and on the average weight of piglets born. Heterozygous sows of LEPRAB/MC4RAG genotype were characterized during that time by the highest weight gains and backfat thickness at P2, and their the piglets born had low birth weight. Over the three reproductive cycles, sows of LEPRAA/MC4RGG and LEPRAB/MC4RGG genotypes produced piglets with significantly higher birth weight compared to sows of LEPRAB/MC4RAG, LEPRBB/MC4RAA and LEPRBB/MC4RGG genotypes.

Polymorphisms in MC1R and ASIP genes and their association with coat color phenotypes in llamas (Lama glama)

The melanocortin 1-receptor (MC1R) and the agouti signaling protein (ASIP) are the major genes controlling the type and location of pigments produced in mammals. In recent years, polymorphisms in these genes have been associated with coat color variation in a number of species. Llamas (Lama glama) are characterized by a great diversity of coat colors. However, the genetic basis of coat color determination is still unknown. Here, we sequenced the MC1R and ASIP genes in llamas and studied the association between the polymorphisms identified and the coat color. Sequence analysis revealed ten nonsynonymous single nucleotide polymorphisms in the MC1R gene. Three main haplotypes were identified, none of which were completely associated to a particular color phenotype. However, significant association was detected between the MC1R*1 haplotype and the presence of pigmented coat (P<0.0001). Compared to the wild allele, MC1R*1 carried two amino acid substitutions, p.G126S and p.V87M. This last replacement occurs at a highly conserved residue among mammals and the same substitution has been previously associated to melanic phenotypes in avian species. Furthermore, two polymorphisms in ASIP exon 4, a 57bp deletion (c.325_381del) and c.292C>T that are both predicted to have a deleterious effect on the protein, were found in homozygous state or combined in most llamas with eumelanic coat.

Allelic variation of melanocortin-1 receptor locus in Saudi indigenous sheep exhibiting different color coats.

ObjectiveThis study was designed to characterize the DNA polymorphisms of the melanocortin-1 receptor (MC1R) gene in indigenous Saudi Arabian sheep breeds exhibiting different color coats, along with individuals of the Sawaknee breed, an exotic sheep imported from Sudan.MethodsThe complete coding region of MC1R gene including parts of 3′ and 5′ untranslated regions was amplified and sequenced from three the indigenous Saudi sheep; Najdi (generally black, n = 41), Naeimi (generally white with brown faces, n = 36) and Herri (generally white, n = 18), in addition to 13 Sawaknee sheep.ResultsFive single nucleotide polymorphisms (SNPs) were detected in the MC1R gene: two led to nonsynonymous mutations (c.218 T>A, p.73 Met>Lys and c.361 G>A, p.121 Asp>Asn) and three led to synonymous mutations (c.429 C>T, p.143 Tyr>Tyr; c.600 T>G, p.200 Leu>Leu, and c.735 C>T, p.245 Ile>Ile). Based on these five SNPs, eight haplotypes representing MC1R Ed and E+ alleles were identified among the studied sheep breeds. The most common haplotype (H3) of the dominant Ed allele was associated with either black or brown coat color in Najdi and Sawaknee sheep, respectively. Two other haplotypes (H6 and H7) of Ed allele, with only the nonsynonymous mutation A218T, were detected for the first time in Saudi indigenous sheep.ConclusionIn addition to investigating the MC1R allelic variation in Saudi indigenous sheep populations, the present study supports the assumption that the two independent nonsynonymous Met73Lys and Asp121Asn mutations in MC1R gene are associated with black or red coat colors in sheep breeds.

Epistatic Interaction of the Melanocortin 1 Receptor and Agouti Signaling Protein Genes Modulates Wool Color in the Brazilian Creole Sheep.

Different pigmentation genes have been associated with color diversity in domestic animal species. The melanocortin 1 receptor (MC1R), agouti signaling protein (ASIP), tyrosinase-related protein 1 (TYRP1), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) genes are candidate genes responsible for variation in wool color among breeds of sheep. Although the influence of these genes has been described in some breeds, in many others the effect of interactions among genes underlying wool color has not been investigated. The Brazilian Creole sheep is a local breed with a wide variety of wool color, ranging from black to white with several intermediate hues. We analyzed in this study the influence of the genes MC1R, ASIP, TYRP1, and KIT on the control of wool color in this breed. A total of 410 samples were analyzed, including 148 white and 262 colored individuals. The MC1R and ASIP polymorphisms were significantly associated with the segregation of either white or colored wool. The dominant MC1R allele (E(D) p.M73K and p.D121N) was present only in colored animals. All white individuals were homozygous for the MC1R recessive allele (E(+)) and carriers of the duplicated copy of ASIP A gene expression assay showed that only the carrier of the duplicated copy of ASIP produces increased levels in skin, not detectable in the single homozygous copy. These results demonstrate that the epistatic interaction of the genotypes in the MC1R and ASIP gene is responsible for the striking color variation in the Creole breed.

Identification and pharmacological analyses of eight naturally occurring caprine melanocortin-1 receptor mutations in three different goat breeds

The melanocortin-1 receptor (MC1R) belongs to the family of seven transmembrane G protein-coupled receptors and plays a central role in animal coat color. We have sequenced the full coding region of 954bp of the MC1R gene in 72 goats of three breeds with different coat colors and identified five missense mutations (K226E, F250V, G255D, V265I, and C267W) and one silent mutation (A61A), among which two haplotypes with complete linkage disequilibrium (A61A and F250V, G255D and V265I) were found. We performed detailed functional studies on the six single and two double mutations in transiently transfected HEK293T cells. We found that none of the mutants had decreased cell surface expression. However, all the mutants except A61A had decreased constitutive activities in the cAMP pathway. Five mutations (F250V, G255D, G267W, A61A/F250V, G255D/V265I) exhibited significant defects in ligand binding and consequent agonist-induced cAMP signaling and ERK1/2 activation. Additionally, K226E, with normal ligand binding affinity and cAMP signaling, showed a significant defect in ERK1/2 activation, exhibiting biased signaling. Co-expression studies showed that the five defective mutants did not affect wild-type MC1R signaling, hence they were not dominant negative. In summary, we provided detailed data of these goat MC1R mutations leading to a better understanding of the role of MC1R mutation and coat color in goats.

Eating Behavior, Low-Frequency Functional Mutations in the Melanocortin-4 Receptor (MC4R) Gene, and Outcomes of Bariatric Operations: A 6-Year Prospective Study.

Data on the effects of eating behavior and genetics on outcomes of gastrointestinal surgery for diabesity have been sparse, often flawed, and controversial. We aimed to assess long-term outcomes of bariatric operations in patients characterized for eating behavior and rare mutations in the melanocortin-4 receptor (MC4R) gene, which is strongly implicated in energy balance. Between 1996 and 2005, 1,264 severely obese Swiss patients underwent current laparoscopic adjustable gastric banding, gastroduodenal bypass, or a hybrid operation. Of these, 872 patients were followed for a minimum of 6 years and were screened for MC4R mutations. Using regression models, we studied relationships between eating behavior and MC4R mutations and postoperative weight loss, complications, and reoperations after 6 years. At baseline, rare functional MC4R mutation carriers exhibited a significantly higher prevalence of binge eating disorder (BED) or loss-of-control eating independent of age, sex, and BMI. Six years after bariatric surgery, the mutation carriers had more major complications than wild-type subjects independent of age, baseline BMI, sex, operation type, and weight loss. Furthermore, high baseline BMI, male sex, BED, and functional MC4R mutations were independent predictors of higher reoperation rates. Sequencing of MC4R and eating typology, combined with stratification for sex and baseline BMI, might significantly improve patient allocation to banding or bypass operations for diabesity as well as reduce both complication and reoperation rates.

Influence of melanocortin-1 receptor (MC1R) polymorphisms on clinical outcomes of patients with metastatic melanoma harboring the BRAF mutation and treated with BRAF inhibitors.

9574Background: In the pigmentation of hair and skin a key role is played by the MC1R gene whose inherited variations are linked with a higher melanoma risk. In melanoma cells, MC1R has a central r...

Association of the FTO (rs9939609) and MC4R (rs17782313) gene polymorphisms with maternal body weight during pregnancy

ObjectiveThe fat mass and obesity (FTO) and melanocortin-4 receptor (MC4R) genes have been consistently associated with the risk for obesity, but few studies have examined the association of the obesity risk alleles with gestational outcomes. The aim of this study was to evaluate the association between single nucleotide polymorphisms (SNPs) of the FTO (rs9939609) and MC4R (rs17782313) genes with changes in maternal body weight during pregnancy. MethodsA sample of 136 pregnant women were followed in a prospective cohort at 5 to 13, 20 to 26, and 30 to 36 wk gestation and 30 to 45 d postpartum. SNPs were analyzed by real-time polymerase chain reaction. Associations between polymorphisms and the outcomes were investigated through longitudinal linear mixed-effects models, multiple linear regression models, and Poisson regression models. ResultsAn SNP in the FTO (rs9939609) gene but not in the MC4R (rs17782313) gene was significantly associated with prepregnancy body mass index (BMI) ≥25 kg/m2 (relative riskFTO = 2.1; 95% confidence interval [CI], 1.4–3.1). SNPs were not statistically associated with excessive gestational weight gain (GWG) or postpartum weight retention (PPWR). For the FTO (rs9939609) gene, women with the AA genotype were heavier in the body weight trajectory of pregnancy, but not when their weight had been adjusted for prepregnancy BMI (βFTO = 0.5 kg; 95% CI, −1.9 to 3). These women started pregnancy heavier but gained less weight (FTO*gestational age = −0.1; 95% CI, −0.2 to 0.03) compared with those who had at least one T allele. ConclusionsThe FTO (rs9939609) AA genotype is positively associated with prepregnancy excessive weight. We found no evidence of a significant effect of the MC4R (rs17782313) or the FTO (rs9939609) gene polymorphisms on the GWG and PPWR.

The effect of interaction between Melanocortin-4 receptor polymorphism and dietary factors on the risk of metabolic syndrome.

BackgroundControversial data is available on the effect of the Melanocortin-4 receptor (MC4R) gene variation on metabolic syndrome (MetS) and ineffectiveness of diet in managing MetS. Effects of the interaction between MC4R polymorphism and dietary factors on MetS were investigated in this study.MethodsSubjects of this nested case-control study were selected from among participants of Tehran Lipid and Glucose Study. Each case (n = 815) was pair matched randomly with a control by age (±5 years) and sex from among those who had not developed ≥1 MetS components at the time that the corresponding case developed MetS. Dietary patterns were determined using factor analysis on 25 foods groups using a valid and reliable, 168-item semi-quantitative food frequency questionnaire (FFQ). MC4R rs12970134 were genotyped by Tetra-Primer ARMS-polymerase chain reaction analysis. Adjusted conditional logistic regression was used to estimate the interactions of SNP with quartiles of dietary factors in relation to MetS. MetS was defined by the modified National Cholesterol Education Program/Adult Treatment panel III.ResultsTwo dietary patterns were extracted. The healthy dietary pattern was loaded heavily on vegetables, legumes, low fat dairy, whole grains, liquid oils and fruits; the western dietary pattern consisted of a high intake of soft drinks, fast foods, sweets, solid oils, red meats, salty snacks, refined grains, high fat dairy, tea and coffee, eggs and poultry. Among A allele carriers, being in the highest quartiles of western dietary pattern score and saturated fatty acid intake had an increased risk of MetS, compared to those in the lowest quartile (P trend = 0.007). Saturated fatty acid intake could modulate the association of A allele carriers of MC4R with MetS (P interaction = 0.03). A significant interaction was observed between rs12970134 with total fat and iron intake on the risk of abdominal obesity (P interaction < 0.05).ConclusionOur findings suggest an interaction between rs12970134 and western dietary pattern, fat and vegetable intakes on the risk of MetS or its components.

Genetic variations of the coding region of the melanocortin receptor 1 (MC1R) gene in the fox.

The melanocortin 1 receptor (MC1R) gene plays an important role in the control of coat colour in mammals. Genetic variation of the MC1R gene and the relationship between genotype and coat colour are not well understood. Studies in the fox may improve our understanding of gene influence on coat colour in dogs and cats. To investigate coat colour associated mutations in the coding region of MC1R gene in foxes. A total of 118 foxes, comprising 70 red foxes (Vulpes vulpes) (19 red, 10 white silver, 29 silver and 12 chocolate foxes) and 48 arctic foxes (Vulpes lagopus) (9 dominant white blue foxes and 39 normal blue foxes) were included in the study. Evaluation of the DNA sequence of the coding region of MC1R gene and its polymorphisms. Eight polymorphic sites (single nucleotide polymorphisms, SNPs) distributed throughout the 954-bp coding region of the fox MC1R gene were detected. Among them, c.13G>T, c.124A>G, c.289G>A, c.373T>C and c.839 T>G were mis-sense mutations, which resulted in codon change of p.G5C, p.N42D, p.V97I, p.C125R and p.F280C, respectively. Mutation and haplotype analysis indicated that c.373T>C was associated with black and brown pigmented phenotypes in foxes, and c.13G>T and c.839T>G were important in distinguishing V. lagopus and V. vulpes. SNP c.373T>C in the coding region of the MC1R gene is probably associated with the brown phenotype of chocolate foxes.

The Use of Analogs of α‐MSH as Tanning Agents for the Prevention of Melanoma

Melanoma, the deadliest form of skin cancer that originates from melanocytes, continues to increase at an annual rate of 4%. Exposure to solar ultraviolet radiation (UV) is causal for melanoma, especially in those with fair skin and poor tanning ability. α‐Melanocyte stimulating hormone (α‐MSH) plays a key role in regulating pigmentation by binding and activating the melanocortin 1 receptor (MC1R) that is expressed on the cell surface of melanocytes. Additionally, activation of the MC1R increases the DNA repair capacity of melanocytes, thereby reducing the DNA damaging effects of UV and mutations, the underlying cause of melanoma. Certain allelic variants of the MC1R gene are associated with red hair, fair skin, and poor tanning ability. This phenotype increases sensitivity to UV and the risk of melanoma. About 30% of the white population in America is heterozygous for one MC1R variant, which increases melanoma risk. The laboratory is developing a melanoma prevention strategy based on utilizing small peptide analogs of α‐MSH that activate the MC1R. Analogs of α‐MSH will be tested for their ability to protect from the deleterious effects of UV by reducing DNA damage, inflammation and sunburn, and apoptosis, and increasing pigmentation in melanocytes contained in cultured human skin substitutes. The tetrapeptides LK 184 at 10 nM, LK 467 at 100 nM, and the tripeptide LK 514 at 1 μM, were tested for their ability to stimulate pigmentation of engineered human skin substitutes (ESS) containing melanocytes. To determine the effects of LK 467, LK 184, and LK 514 on pigmentation, the ESS were treated for 3, 10 or 15 days daily with either peptide. The effects of the three analogs were quantified using Fontana Masson stain to assess their ability to stimulate pigmentation by synthesizing melanin. The analogs showed promising effects in their ability to induce synthesis of melanin, which induces pigmentation. These experiments helped in the progression of determining the efficacy of these analogs in photoprotection and advance their testing in a clinical trial.

Single-nucleotide polymorphism of MC1R, ASIP, and TYRP2 genes in wild and farmed foxes (Vulpes vulpes)

DNA mutations within genes associated with melanogenesis can affect melanin production, leading to dyschromias. Genes that are involved in synthesis of melatonin and may affect the color of skin are melanocortin 1 receptor (MC1R), agouti locus (ASIP), and tyrosinase-related protein-2 (TYRP2). In this study, SNP identification within ASIP, MC1R, and TYRP2 gene fragments in wild and farmed foxes (Vulpes vulpes) was performed. Nine mutations in the ASIP gene which allowed us to distinguish seven SNP profiles, fourteen mutations and five SNP profiles in the MC1R gene, and seven SNP profiles based on four polymorphic nucleotides in the TYRP2 gene were detected. Analyses of obtained profiles indicate that ASIP did not undergo mutations in the wild, and significant variability of SNP profiles was found for TYRP2, with specific haplotypes noted for farm foxes and American and European wild foxes.

Evidence for natural selection at the melanocortin-3 receptor gene in European and African populations.

Obesity is increasing steadily in worldwide prevalence and is known to cause serious health problems in association with type 2 diabetes mellitus (T2DM), including hypertension, stroke, and cardiovascular diseases. According to the thrifty gene hypothesis, the natural selection of obesity-related genes is important during feast and famine because they control body weight and fat levels. Past human adaptations to environmental changes in food supply, lifestyle, and geography may have influenced the selection of genes associated with the metabolism of glucose, lipids, and energy. The melanocortin-3 receptor gene (MC3R) is associated with obesity, with MC3R-deficient mice showing increased fat mass. MC3R variations are also linked with childhood obesity and insulin resistance. Here, we aimed to uncover evidence of selection at MC3R. We performed a three-step method to detect selection at MC3R using HapMap population data. We used Wright's F statistics as a measure of population differentiation, the long-range haplotype test to identify extended haplotypes, and the integrated haplotype score (iHS) to detect selection at MC3R. We observed high population differentiation between European and African populations at two MC3R childhood obesity- and insulin resistance-associated single-nucleotide polymorphisms (rs3746619 and rs3827103) using Wright's F statistics. The iHS revealed evidence of natural selection at MC3R. These findings provide evidence for natural selection at MC3R. Further investigation is warranted into adaptive evolution at T2DM- and obesity-associated genes.

Effect of interactions of polymorphisms in the Melanocortin-4 receptor gene with dietary factors on the risk of obesity and Type 2 diabetes: a systematic review.

To perform a systematic review of the effect of interaction between Melanocortin-4 receptor (MC4R) single nucleotide polymorphisms and diet on the development of obesity and Type 2 diabetes. Environmental factors, such as nutrient intakes or feeding behaviours, can modulate the association of polymorphism in the MC4R gene with obesity and Type 2 diabetes mellitus. A systematic literature search was conducted in the PubMed, Scopus and Google Scholar databases, with a combination of the following keywords: Diet*, nutr*, melanocortin receptor, melanocortin 4 receptor and MC4R. To assess the quality of observational studies, we used a 12-item quality checklist, derived from the STREGA statement. A total of 14 articles were selected based on the inclusion and exclusion criteria. Consumption of highly salty foods and adherence to a Mediterranean dietary pattern can modulate the association between MC4R polymorphisms and the risk of obesity or Type 2 diabetes. Despite the highly contradictory results of intervention studies, after short-term lifestyle interventions, children with variant alleles of MC4R single nucleotide polymorphisms can lose more body weight, compared with non-carriers, although they may have difficulty in maintaining this weight loss in the long-term. To interpret the results of studies on adults, we need further studies. The interaction between MC4R genes with dietary factors plays a significant role in the development of obesity or Type 2 diabetes phenotypes. Early detection of MC4R risk alleles in individuals and modification of their diet based on these results could be an efficient strategy to prevent obesity or diabetes in these subgroups.

Histologic and Phenotypic Factors and MC1R Status Associated with BRAFV600E, BRAFV600K, and NRAS Mutations in a Community-Based Sample of 414 Cutaneous Melanomas

Cutaneous melanomas arise through causal pathways involving interplay between exposure to UV radiation and host factors, resulting in characteristic patterns of driver mutations in BRAF, NRAS, and other genes. To gain clearer insights into the factors contributing to somatic mutation genotypes in melanoma, we collected clinical and epidemiologic data, performed skin examinations, and collected saliva and tumor samples from a community-based series of 414 patients aged 18 to 79, newly diagnosed with cutaneous melanoma. We assessed constitutional DNA for nine common polymorphisms in melanocortin-1 receptor gene (MC1R). Tumor DNA was assessed for somatic mutations in 25 different genes. We observed mutually exclusive mutations in BRAF(V600E) (26%), BRAF(V600K) (8%), BRAF(other) (5%), and NRAS (9%). Compared to patients with BRAF wild-type melanomas, those with BRAF(V600E) mutants were significantly younger, had more nevi but fewer actinic keratoses, were more likely to report a family history of melanoma, and had tumors that were more likely to harbor neval remnants. BRAF(V600K) mutations were also associated with high nevus counts. Both BRAF(V600K) and NRAS mutants were associated with older age but not with high sun exposure. We also found no association between MC1R status and any somatic mutations in this community sample of cutaneous melanomas, contrary to earlier reports.

Synonymous single nucleotide polymorphisms in the MC4R gene that are significantly associated with milk production traits in water buffaloes

Melanocortin-4 receptor (MC4R) is associated with feed intake, growth, fatness, and carcass composition in many domestic animals. The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in MC4R with milk production traits in water buffalo. Eight SNPs were identified by direct polymerase chain reaction sequencing of samples from 18 buffaloes. SNPs were then genotyped using the matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) method in 332 buffaloes. Two of eight SNPs were not in Hardy-Weinberg equilibrium. Based on the SNP data, seven haplotypes were constructed. Three SNPs H1 (AGT), H2 (GAT), and H3 (GAC) accounted for 93.0% of the total individuals. Statistical analysis indicated that the SNP g.1104C>T was significantly associated with milk yield, protein, and fat percentage (P < 0.05). In conclusion, these results provide evidence that polymorphisms in the buffalo MC4R gene are associated with milk production traits and might be potential biomarkers for water buffalo breeding.

Mutations in Melanocortin-3 Receptor Gene and Human Obesity.

The prevalence of obesity calls for novel therapeutic targets. The melanocortin-3 receptor (MC3R) has been increasingly recognized as an important regulator of energy homeostasis and MC3R has been intensively analyzed in molecular genetic studies for obesity-related traits. Twenty-seven MC3R mutations and two common polymorphic variants have been identified so far in different cohorts. The mutant MC3Rs demonstrate multiple defects in functional analysis and can be cataloged into different classes according to receptor life cycle based classification system. Although the pathogenic role of MC3R in human obesity remains controversial, recent findings in the noncanonical signaling pathway of MC3R mutants have provided new insights. Potential therapeutic strategies for obesity related to MC3R mutations are highlighted.