Alternative titles; symbols
HGNC Approved Gene Symbol: MC3R
Cytogenetic location: 20q13.2 Genomic coordinates (GRCh38) : 20:56,248,732-56,249,815 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.2 | {Obesity, severe, susceptibility to, BMIQ9} | 602025 | 3 |
Gantz et al. (1993) identified a third melanocortin receptor that recognizes the core heptapeptide sequence of melanocortins. (See 155555 and 607397 for MC1 and MC2, respectively.) This receptor is expressed in the brain, placenta, and gut tissues, but not in the adrenal cortex or melanocytes.
Cooke et al. (2008) noted that the 361-amino acid MC3R protein is a G protein-coupled receptor with 7 transmembrane domains.
Tarnow et al. (2012) found that translation of MC3R preferentially occurred at the second in-frame ATG codon, resulting in a deduced 323-amino acid protein. The second ATG codon, but not the first, is evolutionarily conserved. Transfection studies in COS-7 cells demonstrated that use of the second ATG codon resulted in a membrane protein.
Park et al. (2014) determined that the first noncoding exon of MC3R directed translation of human MC3R from the second conserved ATG codon. The deduced 323-amino acid protein was expressed as a membrane protein. In transfected polarized MDCK canine kidney cells, MC3R localized to or adjacent to the apical membrane. Experimental lack of exon 1 resulted in MC3R expression initiating from the first and nonconserved ATG codon, producing a 360-amino acid protein with aberrant localization in the cytoplasm. Park et al. (2014) hypothesized that the first ATG may be associated with an upstream ORF that regulates expression of the main ORF from the second ATG.
Cooke et al. (2008) stated that the MC3R gene contains 1 coding exon.
Park et al. (2014) determined that the MC3R gene has 2 exons and spans at least 1.6 kb. The first exon is noncoding.
Gantz et al. (1993) mapped the MC3R gene to chromosome 20q13.2-q13.3 by fluorescence in situ hybridization. By fluorescence in situ hybridization, Magenis et al. (1994) assigned the MC3R gene to 20q13.2; they assigned the homologous gene in the mouse to chromosome 2 by study of an intersubspecific backcross mapping panel. It is noteworthy that the gene for this neural receptor maps to the same region as the locus for benign neonatal epilepsy (EBN1; 121200) in the human and near the El-2 epilepsy susceptibility locus in the mouse. Through study of an interspecific backcross, Malas et al. (1994) also demonstrated that the mouse homolog maps to chromosome 2.
Heisler et al. (2002) found that genetic or pharmacologic blockade of MC4R (155541) and MC3R is sufficient to attenuate the anorectic efficacy of threshold doses of d-FEN (D-fenfluramine), suggesting that drugs targeting these downstream melanocortin pathways may act in part in a manner similar to d-FEN to decrease food intake and body weight with fewer side effects.
Tarnow et al. (2012) found that MC3R that was translated from the second ATG codon, but not the first ATG codon, was expressed at the cell membrane in COS-7 cells and generated cAMP in response to NDP-alpha-MSH stimulation.
Park et al. (2014) found that, in the absence of MC3R, the accessory protein MRAP2 (615410) localized to the cytoplasm in polarized MDCK cells. When coexpressed, MC3R and MRAP2 localized to apical membranes, where they partially overlapped.
Body Mass Index Quantitative Trait Locus 9
In a 13-year-old obese (see BMIQ9; 602025) girl and her father, Lee et al. (2002) identified a heterozygous mutation (I183N; 155540.0001) in the MC3R gene. Functional characterization of the I183N mutant by Tao and Segaloff (2004) showed a complete lack of signaling in response to agonist stimulation.
Mencarelli et al. (2008) sequenced the MC3R gene in 290 obese individuals and 215 normal-weight controls and identified 3 heterozygous mutations present in 3 obese individuals, respectively, that were not present in controls (see, e.g., 155540.0002). Although there were only a limited number of family members available for study, there appeared to be cosegregation of the mutations with the obese phenotype.
Familial genetic studies of noninsulin-dependent diabetes mellitus (NIDDM; 125853) of different human populations, including French Caucasians, suggested evidence for linkage of NIDDM and chromosome 20q13 (see 603694), where the MC3R gene maps. Hani et al. (2001) assessed the MC3R gene for variations in a large cohort of French families with NIDDM and identified thr6-to-lys (T6L) and val81-to-ile (V81I) variants in the MC3R gene. These 2 variants, which were in complete linkage disequilibrium, were also present in nondiabetic controls. Based on association and familial linkage disequilibrium test results, the authors stated that these MC3R gene-coding variants were not associated with diabetes or obesity. Hani et al. (2001) concluded that these variants were marginally associated with insulin and glucose levels during oral glucose tolerance testing in normoglycemic subjects.
Feng et al. (2005) analyzed the MC3R gene in 190 overweight and 160 nonoverweight children and found that 29 (8.2%) children were double homozygous for T6L and V81I variants. The double homozygous children (lys/lys and ile/ile) were significantly heavier (p less than 0.0001), had more body fat (p less than 0.001), and had greater plasma leptin (p less than 0.0001) and insulin concentrations (p less than 0.001) and greater insulin resistance (p less than 0.008) than wildtype or heterozygous children. Both sequence variants were more common in African American than in Caucasian children.
Rutanen et al. (2007) studied the T6L and V81I MC3R polymorphisms in a cross-sectional study of 216 middle-aged nondiabetic Finnish subjects who were offspring of type 2 diabetic patients. Carriers of the lys6 and ile81 alleles had significantly lower rates of lipid oxidation and higher rates of glucose oxidation in the fasting state than subjects with the thr/thr6 and val/val81 genotypes. Rutanen et al. (2007) concluded that SNPs of MC3R may regulate substrate oxidation and first-phase insulin secretion.
Tarnow et al. (2012) reported that translation of MC3R preferentially occurs at the second in-frame ATG codon. The N-terminally truncated protein would lack thr6, making variation at this position unlikely to influence protein function.
Using genomewide linkage and positional mapping of tuberculosis-affected sib pairs in South Africans of mixed racial origin and in Africans from northern Malawi, Cooke et al. (2008) identified a novel putative tuberculosis susceptibility locus on chromosome 20q13.31-q33 (MTBS3; 612929). Detailed SNP mapping of chromosome 20q13.31-q33 in a case-control study of West African subjects revealed evidence of disease association with SNPs in the MC3R and CTSZ (603169) genes. Homozygosity for the A allele of a +241G-A SNP in the MC3R gene (rs3827103), which produces the V81I substitution in the protein (Cooke, 2009), conferred resistance to tuberculosis. In contrast, homozygosity for the C allele of a T-C SNP in the 3-prime UTR of the CTSZ gene (rs34069356) was associated with susceptibility to tuberculosis.
Genetic and pharmacologic studies defined a role for MC4R in the regulation of energy homeostasis. MC3R is expressed at high levels in the hypothalamus. Chen et al. (2000) evaluated the potential role of MC3R in energy homeostasis by studying Mc3r-deficient (Mc3r -/-) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. At the age of 4 to 6 months, Mc3r -/- mice had increased fat mass, reduced lean mass, and higher feed efficiency than wildtype littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r -/- mice were hyperleptinemic, and male Mc3r -/- mice developed mild hyperinsulinemia. They did not show significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r became significantly heavier than Mc4r -/- mice. Chen et al. (2000) concluded that Mc3r and Mc4r serve nonredundant roles in the regulation of energy homeostasis. Cummings and Schwartz (2000) showed that these studies demonstrated that the 2 melanocortin receptor isoforms reduce body weight through distinct and complementary mechanisms. Mc4r regulates food intake and possibly energy expenditure, whereas Mc3r influences feed efficiency and the petitioning of fuel stores into fat.
In a 13-year-old obese girl (BMIQ9; 602025) and her father, Lee et al. (2002) identified a 548T-A transversion, resulting in an ile183-to-asn (I183N) substitution. The MC3R gene was sequenced in 41 unrelated obese children, and 121 DNA samples from nonobese individuals were analyzed for this novel sequence variant by allele-specific PCR. The I183N mutation was found only in the proband and her father, though all 4 family members were obese. The sequence variant was not found in 121 control samples. The proband had a high percentage of body fat (49%), but the father had only 30%. There were no distinguishing phenotypic features. Insulin sensitivity was significantly higher compared to the 40 other obese subjects without MC3R gene mutations. Lee et al. (2002) concluded that differences between phenotypes of the 2 related heterozygotes, and the observation of obesity in other family members without the mutation suggests that obesity results from a varying combination of environmental, behavioral, and multiple genetic factors, even within the same family.
Tao and Segaloff (2004) reported that the I183N mutation completely lacks signaling in response to agonist stimulation, although it binds ligand with normal affinity and with only slightly decreased capacity. Coexpression of the wildtype and I183N MC3Rs showed that I183N does not exert dominant-negative activity on wildtype MC3R. The authors concluded that these results provided support for the hypothesis that MC3R mutation might be a genetic factor that confers susceptibility to obesity, likely due to haploinsufficiency. Further mutations at I183 revealed a discrete requirement for I183 in agonist-induced MC3R activation.
By expression in HEK293 cells, Rached et al. (2004) found that the I183N mutation abolished the cAMP response of MC3R to NDP-MSH stimulation. Coexpression of wildtype protein with increasing concentrations of mutant MC3R demonstrated that the I183N mutation exerts a dominant-negative effect. Confocal microscopy revealed that fluorescence-tagged wildtype, but not mutant, MC3R was expressed at the plasma membrane and in a perinuclear position.
In a 56-year-old woman with a BMI of 39 (BMIQ9; 602025), Mencarelli et al. (2008) identified heterozygosity for a 1004T-G transversion in the MC3R gene, resulting in an ile335-to-ser (I335S) substitution at a highly conserved region. Her 57-year-old brother, who was also heterozygous for the mutation, had a history of early-onset obesity and strong resistance to losing weight despite continuous dieting; in contrast, her 62-year-old sister who did not carry the mutation had a BMI of 26 and no history of obesity. In vitro expression studies demonstrated that the I335S mutation causes complete loss of function. I335S-transfected COS-7 cells showed diffuse cytoplasmic staining, indicating intracellular retention of the receptor.
Mencarelli et al. (2011) identified heterozygosity for the I335S mutation in 2 Caucasian patients with obesity, 1 French and 1 Italian. In vitro functional analysis demonstrated that the I335S mutation resulted in complete inactivation of the receptor.
Chen, A. S., Marsh, D. J., Trumbauer, M. E., Frazier, E. G., Guan, X.-M., Yu, H., Rosenblum, C. I., Vongs, A., Feng, Y., Cao, L., Metzger, J. M., Strack, A. M., and 9 others. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nature Genet. 26: 97-102, 2000. [PubMed: 10973258] [Full Text: https://doi.org/10.1038/79254]
Cooke, G. S., Campbell, S. J., Bennett, S., Lienhardt, C., McAdam, K. P. W. J., Sirugo, G., Sow, O., Gustafson, P., Mwangulu, F., van Helden, P., Fine, P., Hoal, E. G., Hill, A. V. S. Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis. Am. J. Resp. Crit. Care Med. 178: 203-207, 2008. Note: Erratum: Am. J. Resp. Crit. Care Med. 179: 624 only, 2009. [PubMed: 18420963] [Full Text: https://doi.org/10.1164/rccm.200710-1554OC]
Cooke, G. S. Personal Communication. KwaZulu-Natal, South Africa 5/26/2009.
Cummings, D. E., Schwartz, M. W. Melanocortins and body weight: a tale of two receptors. Nature Genet. 26: 8-9, 2000. [PubMed: 10973234] [Full Text: https://doi.org/10.1038/79223]
Feng, N., Young, S. F., Aguilera, G., Puricelli, E., Adler-Wailes, D. C., Sebring, N. G., Yanovski, J. A. Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity. Diabetes 54: 2663-2667, 2005. [PubMed: 16123355] [Full Text: https://doi.org/10.2337/diabetes.54.9.2663]
Gantz, I., Konda, Y., Tashiro, T., Shimoto, Y., Miwa, H., Munzert, G., Watson, S. J., DelValle, J., Yamada, T. Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 268: 8246-8250, 1993. [PubMed: 8463333]
Gantz, I., Tashiro, T., Barcroft, C., Konda, Y., Shimoto, Y., Miwa, H., Glover, T., Munzert, G., Yamada, T. Localization of the genes encoding the melanocortin-2 (adrenocorticotropic hormone) and melanocortin-3 receptors to chromosomes 18p11.2 and 20q13.2-q13.3 by fluorescence in situ hybridization. Genomics 18: 166-167, 1993. [PubMed: 8276410] [Full Text: https://doi.org/10.1006/geno.1993.1448]
Hani, E. H., Dupont, S., Durand, E., Dina, C., Gallina, S., Gantz, I., Froguel, P. Naturally occurring mutations in the melanocortin receptor 3 gene are not associated with type 2 diabetes mellitus in French Caucasians. J. Clin. Endocr. Metab. 86: 2895-2898, 2001. [PubMed: 11397906] [Full Text: https://doi.org/10.1210/jcem.86.6.7589]
Heisler, L. K., Cowley, M. A., Tecott, L. H., Fan, W., Low, M. J., Smart, J. L., Rubinstein, M., Tatro, J. B., Marcus, J. N., Holstege, H., Lee, C. E., Cone, R. D., Elmquist, J. K. Activation of central melanocortin pathways by fenfluramine. Science 297: 609-611, 2002. [PubMed: 12142539] [Full Text: https://doi.org/10.1126/science.1072327]
Lee, Y.-S., Poh, L. K.-S., Loke, K.-Y. A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity. J. Clin. Endocr. Metab. 87: 1423-1426, 2002. [PubMed: 11889220] [Full Text: https://doi.org/10.1210/jcem.87.3.8461]
Magenis, R. E., Smith, L., Nadeau, J. H., Johnson, K. R., Mountjoy, K. G., Cone, R. D. Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human. Mammalian Genome 5: 503-508, 1994. [PubMed: 7949735] [Full Text: https://doi.org/10.1007/BF00369320]
Malas, S., Peters, J., Abbott, C. The genes for endothelin 3, vitamin D 24-hydroxylase, and melanocortin 3 receptor map to distal mouse chromosome 2, in the region of conserved synteny with human chromosome 20. Mammalian Genome 5: 577-579, 1994. [PubMed: 8000144] [Full Text: https://doi.org/10.1007/BF00354934]
Mencarelli , M., Dubern, B., Alili, R., Maestrini, S., Benajiba, L., Tagliaferri, M., Galan, P., Rinaldi, M., Simon, C., Tounian, P., Hercberg, S., Liuzzi, A., Di Blasio, A. M., Clement, K. Rare melanocortin-3 receptor mutations with in vitro functional consequences are associated with human obesity. Hum. Molec. Genet. 20: 392-399, 2011. [PubMed: 21047972] [Full Text: https://doi.org/10.1093/hmg/ddq472]
Mencarelli, M., Walker, G. E., Maestrini, S., Alberti, L., Verti, B., Brunani, A., Petroni, M. L., Tagliaferri, M., Liuzzi, A., Di Blasio, A. M. Sporadic mutations in melanocortin receptor 3 in morbid obese individuals. Europ. J. Hum. Genet. 16: 581-586, 2008. [PubMed: 18231126] [Full Text: https://doi.org/10.1038/sj.ejhg.5202005]
Park, J., Sharma, N., Cutting, G. R. Melanocortin 3 receptor has a 5-prime exon that directs translation of apically localized protein from the second in-frame ATG. Molec. Endocr. 28: 1547-1557, 2014. [PubMed: 25051171] [Full Text: https://doi.org/10.1210/me.2014-1105]
Rached, M., Buronfosse, A., Begeot, M., Penhoat, A. Inactivation and intracellular retention of the human I183N mutated melanocortin 3 receptor associated with obesity. Biochim. Biophys. Acta 1689: 229-234, 2004. [PubMed: 15276649] [Full Text: https://doi.org/10.1016/j.bbadis.2004.03.009]
Rutanen, J., Pihlajamaki, J., Vanttinen, M., Salmenniemi, U., Ruotsalainen, E., Kuulasmaa, T., Kainulainen, S., Laakso, M. Single nucleotide polymorphisms of the melanocortin-3 receptor gene are associated with substrate oxidation and first-phase insulin secretion in offspring of type 2 diabetic subjects. J. Clin. Endocr. Metab. 92: 1112-1117, 2007. Note: Erratum J. Clin. Endocr. Metab. 93: 1506 only, 2008. [PubMed: 17192297] [Full Text: https://doi.org/10.1210/jc.2006-1201]
Tao, Y.-X., Segaloff, D. L. Functional characterization of melanocortin-3 receptor variants identify a loss-of-function mutation involving an amino acid critical for G protein-coupled receptor activation. J. Clin. Endocr. Metab. 89: 3936-3942, 2004. [PubMed: 15292330] [Full Text: https://doi.org/10.1210/jc.2004-0367]
Tarnow, P., Rediger, A., Schulz, A., Gruters, A., Bierbermann, H. Identification of the translation start site of the human melanocortin 3 receptor. Obes. Facts 5: 45-51, 2012. [PubMed: 22433616] [Full Text: https://doi.org/10.1159/000336070]