Melanocortin-4 Receptor Gene Mutations Research Articles

Melanocortin pathways: suppressed and stimulated melanocortin-4 receptor (MC4R).

Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.

Sequence characterization and polymorphism of melanocortin 1 receptor gene in some goat breeds with different coat color of Mongolia.

ObjectiveExtension and Agouti loci play a key role for proportions of eumelanin and pheomelanin in determining coat color in several species, including goat. Mongolian goats exhibit diverse types of coat color phenotypes. In this study, investigation of the melanocortin 1 receptor (MC1R) coding region in different coat colors in Mongolian goats was performed to ascertain the presence of the extension allele.MethodsA total of 105 goat samples representing three goat breeds were collected for this study from middle Mongolia. A 938 base pair (bp) long coding region of the MC1R gene was sequenced for three different breeds with different coat colors (Gobi Gurwan Saikhan: complete black, Zalaa Jinstiin Tsagaan: complete white, Mongolian native goat: admixture of different of coat colors). The genotypes of these goats were obtained from analyzing and comparing the sequencing results.ResultsA total of seven haplotypes defined by five substitution were identified. The five single nucleotide polymorphisms included two synonymous mutations (c.183C>T and c.489G>A) and three missense (non-synonymous) mutations (c.676A>G, c.748T>G, and c.770T>A). Comparison of genotypes frequencies of two common missense mutions using chi-sqaure (x2) test revealed significant differences between coat color groups (p<0.001). A logistic regression analysis additionally suggested highly significant association between genotypes and variation of black versus white uniform combination. Alternatively, most investigated goats (60.4%) belonged to H2 (TGAGT) haplotype.ConclusionAccording to the findings obtained in this study on the investigated coat colors, mutations in MC1R gene may have the crucial role for determining eumelanin and pheomelanin phenotypes. Due to the complication of coat color phenotype, more detailed investigation needed.

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.

Letter to the Editor Adrenal function and MC1R gene analysis in a prepubertal girl with generalized hyperpigmentation:

Letter to the Editor Adrenal function and MC1R gene analysis in a prepubertal girl with generalized hyperpigmentation:

High prevalence of leptin and melanocortin-4 receptor gene mutations in children with severe obesity from Pakistani consanguineous families

Recessive or co-dominant single-gene mutations disrupting leptin melanocortin pathway cause severe obesity and hyperphagia. Since Pakistan has a very high rate of consanguinity, therefore, a significantly higher incidence of monogenic obesity is expected in its population. We have assessed the incidence of LEP and MC4R mutations and associated hormonal profiles, in a cohort of randomly selected Pakistani children with early onset of severe obesity. Sixty two unrelated children of consanguineous parents, with a weight-for-age percentile >97 were recruited in the study. Screening for mutations in the coding regions of LEP and MC4R was performed by direct sequencing. Serum hormone concentrations were determined by immunoassay. LEP mutations were found in 16.1% of the probands. Of these, 9 probands carried the homozygous frameshift mutation, G133_VfsX14, whereas one patient had a homozygous mutation involving deletion of 3 base pairs, (I35del). In these probands, leptin levels were very low or undetectable and insulin levels were increased in 33%. Homozygous MC4R mutations, M161T and I316S, identified separately in 2 subjects (3.2%), were associated with severe obesity, hyperphagia, hyperleptinemia and hyperinsulinemia. The heterozygous M161T sibling had normal body weight and hormone levels and the parents were only mildly overweight. Based on genetic analysis of LEP and MC4R genes only, we elucidated genetic causality of severe obesity in 20% of our patients confirming high prevalence of monogenic form of obesity in this consanguineous population. Co-dominancy of MC4R is exacerbated in this group with non-penetrance of obesity in heterozygous loss-of-function MC4R mutation carriers. The sub-ethnic specificity of LEP mutation, G133_VfsX14, suggests a founder effect.

A novel melanocortin-4 receptor gene mutation in a female patient with severe childhood obesity

This study targeted the identification of mutations of melanocortin-4 receptor gene (MC4R) in obese children. Fifty-one unrelated probands with early onset severe obesity (body mass index (BMI) > 99th percentile; 21 girls, mean age 10.6 +/- 3.6 years) were analyzed for nucleotide variations in the MC4R coding region, by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method followed by direct DNA sequencing. MC4R variants were detected in three patients: the known I169S variant was found in heterozygote state in two patients and a novel heterozygous Y302F mutation was detected in one 12-year-old girl (BMI = 34 kg/m(2), BMI z-score 2.7) who has been overweight since the second year of life and suffered from hyperinsulinemia (at the age of 12: fasting insulin 45 mU/ml, after oral glucose load max. 300 mU/ml). The mutation also appears in the father, although both parents are obese (BMI father: 30.2 kg/m(2); mother: 31.9 kg/m(2)). This novel mutation is located in the functionally important NPXXY motif of the seventh transmembrane domain of the receptor. Functional characterization revealed reduction in cell surface expression and an alteration in signal transduction properties. These results add to the growing list of loss-of-function MC4R mutations in early onset obese patients and suggest an orexigenic effect of novel Y302F mutation.

Anesthetic management for adenotonsillectomy of a child with severe obesity due to homozygous melanocortin-4 receptor gene mutations

Pediatric AnesthesiaVolume 19, Issue 2 p. 195-196 Anesthetic management for adenotonsillectomy of a child with severe obesity due to homozygous melanocortin-4 receptor gene mutations J. Nick Pratap, J. Nick Pratap Department of Anaesthesia, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK (email: al-tpp@dsl.pipex.com)Search for more papers by this authorCharoo Sekhri, Charoo Sekhri Department of Anaesthesia, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK (email: al-tpp@dsl.pipex.com)Search for more papers by this authorAdrian R. Lloyd-Thomas, Adrian R. Lloyd-Thomas Department of Anaesthesia, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK (email: al-tpp@dsl.pipex.com)Search for more papers by this author J. Nick Pratap, J. Nick Pratap Department of Anaesthesia, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK (email: al-tpp@dsl.pipex.com)Search for more papers by this authorCharoo Sekhri, Charoo Sekhri Department of Anaesthesia, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK (email: al-tpp@dsl.pipex.com)Search for more papers by this authorAdrian R. Lloyd-Thomas, Adrian R. Lloyd-Thomas Department of Anaesthesia, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK (email: al-tpp@dsl.pipex.com)Search for more papers by this author First published: 27 January 2009 https://doi.org/10.1111/j.1460-9592.2008.02923.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume19, Issue2February 2009Pages 195-196 RelatedInformation

Novel melanocortin 4 receptor gene mutations in severely obese children

Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. The significance of MC4R mutations in Asian obese populations has not been adequately examined. The objective of this study was to determine the role of MC4R mutations in severely obese Asian children. We screened 227 obese local children and adolescents for MC4R gene mutations by polymerase chain reaction and direct sequencing. We identified three mutations in three subjects: 4 bp deletion from nucleotides 631-634 (c.631-634delCTCT), Tyr157Ser (c.470 A > C) and 1 bp deletion at nucleotide 976 (c.976delT) (1.32% of study subjects). The latter two mutations are novel. The Tyr157Ser mutation was not found in 188 non-obese controls using restriction enzyme digest analysis. In vitro transient transfection studies supported the pathogenic role of both novel mutations Tyr157Ser and c.976delT, where the signalling activities of the mutant receptors were impaired. Heterozygous MC4R mutations were associated with early-onset severe obesity, and homozygosity of the MC4R mutation Tyr157Ser resulted in morbid obesity. MC4R mutations result in an autosomal codominant form of obesity with variable expressivity. MC4R deficiency is not as common among the obese children in this study compared to other populations. Family studies revealed that adults heterozygous for the mutations were less obese compared to the children. We hypothesize that this may be due to amelioration of phenotype severity with age, genetic anticipation or difference in exposure to modifying factors at critical stages of childhood such as the environment.

Prevalence, Spectrum, and Functional Characterization of Melanocortin-4 Receptor Gene Mutations in a Representative Population-Based Sample and Obese Adults from Germany

Autosomal dominant inheritance of mutations in the melanocortin-4 receptor gene (MC4R) is currently regarded as the most relevant genetic cause for extreme obesity and affects 2-4% of extremely obese individuals. Our objective was to assess the relevance of MC4R mutations in a German population-based sample. We conducted a mutation screen of the MC4R gene by capillary electrophoresis-based single-strand conformation polymorphism analysis and denaturing HPLC. Subjects included 4068 individuals of a German population-based study group [Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4 (KORA-S4); i.e. Cooperative Health Research in the Region of Augsburg] and 1003 German obese adults (body mass index >or= 30 kg/m(2)). Samples with aberrant capillary electrophoresis-based single-strand conformation polymorphism analysis/denaturing HPLC patterns were resequenced. Functional studies including agonistic receptor stimulation (Nle-D-Phe-alpha-, alpha-, and beta-MSH) and cell surface expression assays were performed. Sixteen (six novel) coding nonsynonymous mutations were detected in 27 heterozygous individuals of KORA-S4. Four of the mutation alleles led to impaired receptor function in vitro; however, none of these six heterozygous mutation carriers was obese (body mass index >or= 30 kg/m(2)). In the obese adults, six coding nonsynonymous and a nonsense mutation were detected in 13 individuals. Only the nonsense mutation allele entailed impaired receptor function. Our study depicts prevalence, spectrum, and functional characterization of MC4R mutations in the German population-based sample KORA-S4. In this epidemiological study group, individuals heterozygous for nonsynonymous MC4R mutation alleles entailing impaired function were not obese. Furthermore, nonsynonymous MC4R mutations causing impaired receptor function were rare in German obese adults (two in 1003 = 0.2%).

A role for β-melanocyte-stimulating hormone in human body-weight regulation

Pro-opiomelanocortin (POMC) expressing neurons mediate the regulation of orexigenic drive by peripheral hormones such as leptin, cholecystokinin, ghrelin, and insulin. Most research effort has focused on alpha-melanocyte-stimulating hormone (alpha-MSH) as the predominant POMC-derived neuropeptide in the central regulation of human energy balance and body weight. Here we report a missense mutation within the coding region of the POMC-derived peptide beta-MSH (Y5C-beta-MSH) and its association with early-onset human obesity. In vitro and in vivo data as well as postmortem human brain studies indicate that the POMC-derived neuropeptide beta-MSH plays a critical role in the hypothalamic control of body weight in humans.

Double Leptin and Melanocortin-4 Receptor Gene Mutations Have an Additive Effect on Fat Mass and Are Associated with Reduced Effects of Leptin on Weight Loss and Food Intake

Melanocortin-4 receptors (MC4Rs) are involved in the regulation of food intake, sympathetic nervous activity, and adrenal and thyroid function by leptin. The role of MC4Rs in regulating energy balance by leptin was investigated using double heterozygote or homozygous leptin (Lep(ob)) and Mc4r gene mutant mice. Double heterozygous or homozygous mutants were generated by crossing MC4R knockout (Mc4r-/-) mice, backcrossed onto C57BL/6J, with B6.V-Lep(ob) mice. Energy expenditure was measured using indirect calorimetry. The effect of leptin on food intake, weight loss, insulin, and corticosterone was compared for Lep(ob)/Lep(ob)Mc4r-/- mice and Lep(ob)/Lep(ob) mice. Double heterozygous and homozygous mutants exhibited an additive effect on fat mass. The 2-fold increase in body weight associated with severe obesity of Lep(ob)/Lep(ob) mice was associated with a significantly higher 24 h total and resting energy expenditure. The effect of obesity on energy expenditure was attenuated by 50% in Lep(ob)/Lep(ob) Mc4r+/- and Lep(ob)/Lep(ob) Mc4r-/- mice. Loss of MC4Rs did not affect basal food intake of Lep(ob)/Lep(ob) mice but was associated with partial leptin resistance in terms of food intake and weight loss. Leptin suppression of insulin and corticosterone in Lep(ob)/Lep(ob) mice were not significantly affected by Mc4r genotype. These results suggest a complex interaction between the Lep and Mc4r genes in energy homeostasis and suggest that MC4Rs retain significant anti-obesity function in the obese leptin-deficient state. Increased adiposity with double mutations may involve a reduction in energy expenditure. MC4Rs might have a modest role in the regulation of energy balance by exogenously administered leptin, primarily effecting food intake.

Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations.

Recently, Branson and coworkers reported a strong association between binge-eating disorder (BED) and variants in the melanocortin-4 receptor gene (MC4R). In the current study, we compared the eating behavior of 43 obese probands with functionally relevant MC4R mutations and of 35 polymorphism carriers (V103I or I251L) with wild-type carriers. The module for eating disorders of the Composite International Diagnostic Interview was used to identify binge-eating behavior. The Three-Factor Eating Questionnaire and the Leeds Food Frequency Questionnaire were used to assess restrained eating, disinhibition, hunger and percent total energy intake as fat. No significant differences between carriers of MC4R variants and wild-type carriers were detected. In particular, we found no evidence for an increased rate of binge-eating behavior in obese carriers of MC4R variants. Our findings do not support the strong association between BED and MC4R carrier status.

Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese finnish children and adults.

Two Finnish cohorts, comprising 56 children with severe early-onset obesity (relative weight for height greater than or equal to +70% before age 10) and 252 morbidly obese adults (body mass index, > or = 40 kg/m(2)), were screened for melanocortin-4 receptor (MC4R) mutations. We identified a pathogenic mutation (S127L) in one child, causing severe early-onset obesity. We describe the phenotype of this particular mutation for the first time. We also identified a novel (I226T) polymorphism in the coding and two new variations (-439delGC and 1059C>T) outside the coding region of the MC4R gene. Three previously described polymorphisms (V103I, T112M, and I125L) were identified. In vitro functional studies of variants T112M, S127L, and I226T supported a pathogenic role of the S127L mutation, because signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired. The S127L mutation did not affect receptor inhibition by the antagonist agouti-related protein. Localization of the three variant receptors was similar to that of wild type. In conclusion, a pathogenic MC4R mutation was found among subjects with severe early-onset obesity but not among morbidly obese adults. Impaired function of the S127L receptor was due to reduced activation, not a defect of protein transport to the cell membrane.

Melanocortin-4 Receptor Gene Mutations and Obesity

Obesity is caused by the interaction of multiple genetic and environmental factors. Several genes involved with appetite have been identified: α-melanocyte-stimulating hormone is an anorexigenic peptide and a potent agonist of the melanocortin-4 receptor (MC4R). In 2 studies, researchers evaluated the link between MC4R gene mutations and obesity. In the first study, 5.8% of 500 subjects with severe early-onset obesity (before age 10) had mutations …