Alternative titles; symbols
HGNC Approved Gene Symbol: MTNR1B
Cytogenetic location: 11q14.3 Genomic coordinates (GRCh38): 11:92,969,651-92,984,960 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q14.3 | {Diabetes mellitus, type 2, susceptibility to} | 125853 | Autosomal dominant | 3 |
Reppert et al. (1995) cloned human MTNR1B. The deduced 362-amino acid protein has a calculated molecular mass of 40.2 kD. It belongs to the G protein-coupled receptor family and has 7 transmembrane domains, an extracellular N-terminal domain, and an intracellular C-terminal domain. Comparative RT-PCR showed that MTNR1B was expressed in retina and, to a lesser extent, in brain.
Reppert et al. (1995) showed that COS-1 cells expressing human MEL1B bound radiolabeled melatonin. Mouse fibroblasts expressing MEL1B accumulated intracellular cAMP in response to forskolin-mediated adenylate cyclase (see 103072) activation, and melatonin binding reversed forskolin-mediated cAMP accumulation.
Levoye et al. (2006) noted that the melatonin receptors MTNR1A (600665) and MTNR1B share a high degree of sequence homology with GPR50 (300207). They showed that GPR50 heterodimerized with both melatonin receptors in vitro and in intact cells. Association of GPR50 with MTNR1B did not modify MTNR1B function, but association of GPR50 with MTNR1A abolished high-affinity agonist binding and G protein coupling to MTNR1A.
Reppert et al. (1995) determined that the MTNR1B gene contains 2 coding exons that span about 10 kb.
Crystal Structure
Johansson et al. (2019) reported XFEL structures of the human MT2 receptor in complex with the agonists 2-phenylmelatonin and ramelteon at resolutions of 2.8 angstroms and 3.3 angstroms, respectively, along with 2 structures of function-related mutants: H208(5.46)A and N86(2.50)D, obtained in complex with 2-phenylmelatonin. Comparison of the structures of MT2 with a published structure of MT1 (600665) (Stauch et al., 2019) revealed that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in tritiated melatonin dissociation kinetics that provided insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel was observed in both MT1 and MT2, but in addition the MT2 structures revealed a narrow opening towards the solvent in the extracellular part of the receptor. Johansson et al. (2019) provided functional and kinetic data that supported a prominent role for intramembrane ligand entry in both receptors, and suggested that there might also be an extracellular entry path in MT2.
By PCR analysis of human-rodent somatic cell hybrids, Reppert et al. (1995) mapped the MTNR1B gene to chromosome 11q21-q22.
Type 2 Diabetes Mellitus
Bonnefond et al. (2012) performed large-scale exon resequencing of the MTNR1B gene in 7,632 Europeans, including 2,186 individuals with type 2 diabetes (T2D; 125853), and identified 40 nonsynonymous variants, including 36 rare variants associated with T2D. Functional investigation revealed that 14 of the variants were nonfunctional and rare, and that 4 of them were rare with complete loss of melatonin-binding and signaling capabilities (A42P, 600804.0001; L60R, 600804.0002; P95L, 600804.0003; and Y308S, 600804.0004). Genotyping the 4 complete loss-of-function variants as a pool in 11,854 individuals, including 5,967 with T2D, demonstrated their association with T2D (odds ratio, 3.88; p = 5.37 x 10(-3)). Bonnefond et al. (2012) concluded that their study established a firm functional link between MTNR1B and T2D risk.
Associations Pending Confirmation
For discussion of a possible association between variation in the MTNR1B gene and fasting plasma glucose levels, see FGQTL3 (613233).
In a large-scale exon resequencing of the MTNR1B gene in 7,632 Europeans, including 2,186 individuals with type 2 diabetes (T2D; 125853), Bonnefond et al. (2012) identified a G-to-C transversion at genomic coordinate chr11:92,342,663 (NCBI36), resulting in an ala42-to-pro (A42P) substitution in the predicted transmembrane domain I. The mutation is rare, with a minor allele frequency of less than 0.1%, and functional analysis in HEK293 cells demonstrated that the A42P variant has no I(125)MLT binding ability and does not activate downstream G(i)-protein-dependent or ERK1 (601795)/2 (176948) signaling pathways. Analysis of this and 3 other complete loss-of-function MTNR1B variants (L60R, 600804.0002; P95L, 600804.0003; and Y308S, 600804.0004) as a pool in 11,854 individuals, including 5,967 with T2D, demonstrated their association with T2D (odds ratio, 3.88; p = 5.37 x 10(-3)).
In a large-scale exon resequencing of the MTNR1B gene in 7,632 Europeans, including 2,186 individuals with type 2 diabetes (T2D; 125853), Bonnefond et al. (2012) identified a T-to-G transversion at genomic coordinate chr11:92,342,718 (NCBI36), resulting in a leu60-to-arg (L60R) substitution in the predicted transmembrane domain I. The mutation is rare, with a minor allele frequency of less than 0.1%, and functional analysis in HEK293 cells demonstrated that the L60R variant has no I(125)MLT binding ability and does not activate downstream G(i)-protein-dependent or ERK1 (601795)/2 (176948) signaling pathways. Analysis of this and 3 other complete loss-of-function MTNR1B variants (A42P, 600804.0001; P95L, 600804.0003; and Y308S, 600804.0004) as a pool in 11,854 individuals, including 5,967 with T2D, demonstrated their association with T2D (odds ratio, 3.88; p = 5.37 x 10(-3)).
In a large-scale exon resequencing of the MTNR1B gene in 7,632 Europeans, including 2,186 individuals with type 2 diabetes (T2D; 125853), Bonnefond et al. (2012) identified a C-to-T transition at genomic coordinate chr11:92,354,321 (NCBI36), resulting in a pro95-to-leu (P95L) substitution in the predicted transmembrane domain II. The mutation is rare, with a minor allele frequency of less than 0.1%, and functional analysis in HEK293 cells demonstrated that the P95L variant has no I(125)MLT binding ability and does not activate downstream G(i)-protein-dependent or ERK1 (601795)/2 (176948) signaling pathways. Analysis of this and 3 other complete loss-of-function MTNR1B variants (A42P, 600804.0001; L60R, 600804.0002; and Y308S, 600804.0004) as a pool in 11,854 individuals, including 5,967 with T2D, demonstrated their association with T2D (odds ratio, 3.88; p = 5.37 x 10(-3)).
In a large-scale exon resequencing of the MTNR1B gene in 7,632 Europeans, including 2,186 individuals with type 2 diabetes (T2D; 125853), Bonnefond et al. (2012) identified a A-to-C transversion at genomic coordinate chr11:92,354,963 (NCBI36), resulting in a tyr308-to-ser (Y308S) substitution within a conserved motif in the predicted transmembrane domain VII. The mutation is rare, with a minor allele frequency of less than 0.1%, and functional analysis in HEK293 cells demonstrated that the Y308S variant has no I(125)MLT binding ability and does not activate downstream G(i)-protein-dependent or ERK1 (601795)/2 (176948) signaling pathways. Analysis of this and 3 other complete loss-of-function MTNR1B variants (A42P, 600804.0001; L60R, 600804.0002; and P95L, 600804.0003) as a pool in 11,854 individuals, including 5,967 with T2D, demonstrated their association with T2D (odds ratio, 3.88; p = 5.37 x 10(-3)).
Bonnefond, A., Clement, N., Fawcett, K., Yengo, L., Vaillant, E., Guillaume, J.-L., Dechaume, A., Payne, F., Roussel, R., Czernichow, S., Hercberg, S., Hadjadj, S., and 16 others. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nature Genet. 44: 297-301, 2012. [PubMed: 22286214] [Full Text: https://doi.org/10.1038/ng.1053]
Johansson, L. C., Stauch, B., McCorvy, J. D., Han, G. W., Patel, N., Huang, X.-P., Batyuk, A., Gati, C., Slocum, S. T., Li, C., Grandner, J. M., Hao, S., and 12 others. XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity. Nature 569: 289-292, 2019. [PubMed: 31019305] [Full Text: https://doi.org/10.1038/s41586-019-1144-0]
Levoye, A., Dam, J., Ayoub, M. A., Guillaume, J.-L., Couturier, C., Delagrange, P., Jockers, R. The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization. EMBO J. 25: 3012-3023, 2006. [PubMed: 16778767] [Full Text: https://doi.org/10.1038/sj.emboj.7601193]
Reppert, S. M., Godson, C., Mahle, C. D., Weaver, D. R., Slaugenhaupt, S. A., Gusella, J. F. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel(1b) melatonin receptor. Proc. Nat. Acad. Sci. 92: 8734-8738, 1995. [PubMed: 7568007] [Full Text: https://doi.org/10.1073/pnas.92.19.8734]
Stauch, B., Johansson, L. C., McCorvy, J. D., Patel, N., Han, G. W., Huang, X. P., Gati, C., Batyuk, A., Slocum, S. T., Ishchenko, A., Brehm, W., White, T. A., and 15 others. Structural basis of ligand recognition at the human MT1 melatonin receptor. Nature 569: 284-288, 2019. [PubMed: 31019306] [Full Text: https://doi.org/10.1038/s41586-019-1141-3]