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|Coordinate||66,859,488 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||melanocortin 4 receptor|
|Chromosomal Location||66,857,715-66,860,472 bp (-)|
|MGI Phenotype||Mutations in this gene result in hyperglycemia and weight gain.|
|Amino Acid Change||Isoleucine changed to Phenylalanine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000054776]|
AA Change: I185F
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Phenotypic Category||growth/size, increase in body weight|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Last Updated||12/08/2016 11:14 AM by Katherine Timer|
|Record Created||09/16/2016 9:17 PM|
The Big_boned phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R4806, some of which showed increased body weights compared to wild-type mice (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 63 mutations. The increased body weight phenotype was linked to two genes: Mc4r and Psmg2. The mutation in Mc4r is presumed to be causative as the phenotype of the Big_boned mice mimics that of other Mc4r alleles (see MGI for a list of Mc4r alleles as well as the record for Southbeach). The Mc4r mutation is an A to T transversion at base pair 66,859,488 (v38) on chromosome 18, or base pair 1,000 in the GenBank genomic region NC_000084 for the Mc4r gene. Linkage was found with an additive model of inheritance (P = 6.809 x 10-6), wherein one variant homozygote and seven heterozygotes departed phenotypically from three homozygous reference mice (Figure 2).
The mutation corresponds to residue 1000 in the mRNA sequence NM_016977 within exon 1 of 1 total exons.
The mutated nucleotide is indicated in red. The mutation results in an isoleucine (I) to phenylalanine (F) substitution at position 185 (I185F) in the MC4R protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 1.00) (1).
MC4R belongs to the family of melanocortin receptors, which are seven transmembrane (TM) spanning G-protein coupled receptors (GPCRs) (Figure 3 & 4). MC4R activates the heterotrimeric G-protein Gs, which stimulates adenylyl cyclase production of cAMP from ATP (2). GPCRs have seven transmembrane helices connected by loops, and ligand binding occurs at extracellular loops facilitated by specific transmembrane helices. Based on a pure modeling approach modeled upon the crystal structure of bovine rhodopsin, another GPCR, residues in transmembrane domain (TM)3, TM4, TM5 and TM6 were predicted to flank the ligand binding site. Extracellular loops 2 and 3 also participate in docking of ligand (3). Interestingly, TM1 and TM7 were not predicted to contribute to ligand binding, although F284 was found at the edge of the ligand-binding pocket (3). The third intracellular loop of MC4R is predicted to form an α-helical segment, and play an important role in coupling the receptor to Gs. The Big_boned mutation results in an isoleucine (I) to phenylalanine (F) substitution at position 185 in TM4, two amino acids from the extracellular loop connecting TM4 and TM5.
Please see the record for Southbeach for more information about Mc4r.
A main mechanism of energy balance regulation involves the control of signaling by the central melanocortin receptors (MCRs) MC3R and MC4R within a defined hypothalamic neural network. Two sets of neurons in the arcuate nucleus (a region surrounding the third ventricle in the most ventral portion of the hypothalamus) act as sensors of whole-body energy status and initiate signals to maintain energy stores at a constant level. The Agrp/Npy neurons (producing Agrp and neuropeptide Y) are inhibited by the leptin peptide (see the record for Potbelly) by signaling through the leptin receptor (see the record for Business_class), while Pomc/Cart neurons (producing Pomc; its proteolytic products and cocaine- and amphetamine-regulated transcript) are stimulated by leptin (4-6). Both Agrp/Npy and Pomc/Cart neurons synapse onto MC4R-expressing neurons (4;7). Thus, when leptin levels are low, Agrp/Npy neurons are activated and Pomc/Cart neurons are inhibited, producing Agrp but not Pomc, and resulting in inhibition of MC4R and increased food intake.
In humans, mutations in MC4R are associated with obesity (OMIM #601665). Human patients with MC4R mutations exhibit increased body mass index, increased appetite, increased height, increased lean mass, increased bone mineral density and hyperinsulinemia (8). With the exception of increased bone mineral density, these phenotypes are recapitulated in Mc4r null mice (9).
The obesity phenotype observed in the Big_boned mice mirrored that of other ENU-induced mutations attributed to Mc4r, including Southbeach and Fatboy (MGI:2671841) (10), confirming that the Mc4r mutation in Big_boned was causative. The localization, expression, and function of the MC4RBig_boned protein have not been determined; however, the obesity phenotype of the Big_boned mice indicates that the mutation results in loss of MC4R function.
Big_boned(F):5'- ATGGTCAAGGTAATCGCCCC -3'
Big_boned(R):5'- GAGCTTCACCGTGAACATTG -3'
Big_boned_seq(F):5'- AAGGTAATCGCCCCCTTCATG -3'
Big_boned_seq(R):5'- GAGCTTCACCGTGAACATTGATAATG -3'
1. Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., and Sunyaev, S. R. (2010) A Method and Server for Predicting Damaging Missense Mutations. Nat Methods. 7, 248-249.
2. Gantz, I., Miwa, H., Konda, Y., Shimoto, Y., Tashiro, T., Watson, S. J., DelValle, J., and Yamada, T. (1993) Molecular Cloning, Expression, and Gene Localization of a Fourth Melanocortin Receptor. J Biol Chem. 268, 15174-15179.
3. Yang, X., Wang, Z., Dong, W., Ling, L., Yang, H., and Chen, R. (2003) Modeling and Docking of the Three-Dimensional Structure of the Human Melanocortin 4 Receptor. J Protein Chem. 22, 335-344.
4. Hahn, T. M., Breininger, J. F., Baskin, D. G., and Schwartz, M. W. (1998) Coexpression of Agrp and NPY in Fasting-Activated Hypothalamic Neurons. Nat Neurosci. 1, 271-272.
5. Cowley, M. A., Smart, J. L., Rubinstein, M., Cerdan, M. G., Diano, S., Horvath, T. L., Cone, R. D., and Low, M. J. (2001) Leptin Activates Anorexigenic POMC Neurons through a Neural Network in the Arcuate Nucleus. Nature. 411, 480-484.
6. Kristensen, P., Judge, M. E., Thim, L., Ribel, U., Christjansen, K. N., Wulff, B. S., Clausen, J. T., Jensen, P. B., Madsen, O. D., Vrang, N., Larsen, P. J., and Hastrup, S. (1998) Hypothalamic CART is a New Anorectic Peptide Regulated by Leptin. Nature. 393, 72-76.
7. Bagnol, D., Lu, X. Y., Kaelin, C. B., Day, H. E., Ollmann, M., Gantz, I., Akil, H., Barsh, G. S., and Watson, S. J. (1999) Anatomy of an Endogenous Antagonist: Relationship between Agouti-Related Protein and Proopiomelanocortin in Brain. J Neurosci. 19, RC26.
8. Farooqi, I. S., Keogh, J. M., Yeo, G. S., Lank, E. J., Cheetham, T., and O'Rahilly, S. (2003) Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene. N Engl J Med. 348, 1085-1095.
9. Huszar, D., Lynch, C. A., Fairchild-Huntress, V., Dunmore, J. H., Fang, Q., Berkemeier, L. R., Gu, W., Kesterson, R. A., Boston, B. A., Cone, R. D., Smith, F. J., Campfield, L. A., Burn, P., and Lee, F. (1997) Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice. Cell. 88, 131-141.
|Authors||Emre Turer and Bruce Beutler|
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