MTNR1B

General Information

Full gene name:melatonin receptor 1B Entrez Gene ID:4544 Location:11q21-q22 Synonyms:MT2, MEL-1B-R, FGQTL2 Type:protein-coding

User SNPs

SNPs given by the user that are near or inside this gene:

SNP	Distance (bp)	Direction
rs10830963	0	within

NCBI Summary

This gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This gene product is an integral membrane protein that is a G-protein coupled, 7-transmembrane receptor. It is found primarily in the retina and brain although this detection requires RT-PCR. It is thought to participate in light-dependent functions in the retina and may be involved in the neurobiological effects of melatonin. [provided by RefSeq, Jul 2008]

OMIM

OMIM ID:`OMIM ID 600804 `_

Allelic Variants (Selected Examples)

.0001 DIABETES MELLITUS, TYPE 2, SUSCEPTIBILITY TO

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)).

.0002 DIABETES MELLITUS, TYPE 2, SUSCEPTIBILITY TO

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)).

.0003 DIABETES MELLITUS, TYPE 2, SUSCEPTIBILITY TO

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)).

.0004 DIABETES MELLITUS, TYPE 2, SUSCEPTIBILITY TO

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)).

NCBI Phenotypes

• Gene Reviews
• Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.
• Genome-wide screen for metabolic syndrome susceptibility Loci reveals strong lipid gene contribution but no evidence for common genetic basis for clustering of metabolic syndrome traits.
• A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk.
• Variants in MTNR1B influence fasting glucose levels.
• A genome-wide association study of gestational diabetes mellitus in Korean women.
• Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.
• Genome-wide association study identifies multiple loci influencing human serum metabolite levels.
• Diabetes mellitus type 2
• Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
• OMIM
• Common genetic variation near melatonin receptor MTNR1B contributes to raised plasma glucose and increased risk of type 2 diabetes among Indian Asians and European Caucasians.
• New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
• GTR
• Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits.
• Fasting glucose GWAS candidate region analysis across ethnic groups in the Multiethnic Study of Atherosclerosis (MESA).
• NHGRI GWA Catalog

Gene Ontology

• G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
• regulation of insulin secretion
• glucose homeostasis
• melatonin receptor activity
• synaptic transmission
• G-protein coupled receptor activity
• integral to plasma membrane
• plasma membrane

KEGG Pathways

• Neuroactive ligand-receptor interaction

GeneRIFs

• Results suggest that common genetic variation in the MTNR1a and 1b genes may contribute to breast cancer susceptibility, and that associations may vary by menopausal status. [PMID 22138747]
• Expression in cultured skin cells. [PMID 12767050]
• variants in MTNR1B confer pancreatic beta-cell dysfunction [PMID 20597807]
• MT(2) melatonin receptor may have undergone a selective pressure in response to global variation in sunshine duration. selection of rs4753426C allele would insure that carriers adapted to local daily and seasonal rhythms more quickly [PMID 20050988]
• Observational study of genotype prevalence. (HuGE Navigator) [PMID 20050988]
• The rs10830963 polymorphism in MTNR1B was associated with increased fasting glucose and risk of impaired fasting glucose in Chinese children and adolescents. [PMID 21701235]
• Study identified six non-synonymous mutations for MTNR1A and ten for MTNR1B in autism spectrum disorders patients . The majority of these variations altered receptor function. [PMID 20657642]
• Meta-analysis and genome-wide association study of gene-disease association. (HuGE Navigator) [PMID 19060907]
• Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. [PMID 19060907]
• There were significant associations between the two genetic variants (rs10830963 and rs1387153) of the melatonin receptor 1B gene and gestational diabetes mellitus. [PMID 21658282]
• role of proline residues in structure & function of the MT2 receptor; results indicate residues P174, P212 & P266 are important for ligand binding and/or signaling of the MT2 receptor [PMID 18544139]
• There is no effect by the common gene variant rs10830963 of the melatonin receptor 1B on the association between sleep disturbances and type 2 diabetes. [PMID 21380592]
• Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. [PMID 22286214]
• Polymorphisms of the promoter of MTNR1B gene were associated with AIS, but not with the curve severity in AIS patients. This suggested that MTNR1B was an AIS predisposition gene. [PMID 17632395]
• These data suggest a possible link between circadian rhythm regulation and glucose homeostasis through the melatonin signaling pathway. [PMID 19060909]
• Observational study of gene-disease association, gene-gene interaction, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [PMID 20879858]
• Melatonin synergizes with oxytocin to promote myometrial cell contractions in vitro, which in vivo would promote coordinated and forceful contractions of the late term pregnant uterus necessary for parturition. [PMID 19001515]
• melatonin receptor type 1B polymorphism is associated with the presence of rheumatoid factor in Korean rheumatoid arthritis [PMID 16098099]
• The results of this study suggested that the Single nucleotide polymorphisms MT(2) receptor gene influence the risk of recurrent depressive disorder. [PMID 21353709]
• These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of type 2 diabetes. [PMID 19060908]
• Six SNP(rs7754840 in CDKAL1, rs391300 in SRR, rs2383208 in CDKN2A/2B, rs4402960 in IGF2BP2, rs10830963 in MTNR1B, rs4607517 in GCK)risk alleles of type 2 diabetes were associated with GDM in pregnant Chinese women. [PMID 22096510]
• Melatonin has a modulating effect on dopaminergic neurotransmission in the brain. Read More: http://informahealthcare.com/doi/full/10.3109/15622975.2010.496870 [PMID 20726823]
• Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [PMID 20726823]
• Variations and single-nucleotide polymorphisms are associated in variations in fasting plasma glucose and an increased risk of type 2 diabetes. [PMID 19533084]
• Study showed that SNPs from GCK, G6PC2 and MTNR1B modulated the fasting glucose levels in the normoglycaemic population while SNPs from G6PC2 and GCKR was associated with type 2 diabetes. [PMID 20668700]
• Observational study, meta-analysis, and genome-wide association study of gene-disease association. (HuGE Navigator) [PMID 20858683]
• A common variant in the MTNR1B gene is associated with an increased risk of type 2 diabetes and increased fasting plasma glucose in Han Chinese. [PMID 19241057]
• A common variant in MTNR1B was associated with fasting glucose, HbA1C and HOMA-B but not with sleep status in Chinese Hans from Shanghai. [PMID 20398260]
• residues N268 and A275 in TM6 as well as residues V291 and L295 in TM7 are essential for 2-iodomelatonin binding to the MT2 receptor [PMID 15913560]
• MT2 receptor is involved in mediating the insulin- and cGMP-inhibiting action of melatonin in panreatic beta cells. [PMID 18363673]
• Observational study of gene-disease association, gene-gene interaction, and gene-environment interaction. (HuGE Navigator) [PMID 20889853]
• The G-allele of rs10830693 in the MTNR1B gene was significantly related to glucose levels, while an impact of this genetic variant on the changes in glucose metabolism in children participating in a lifestyle intervention was not observable. [PMID 21366812]
• Fasting glucose association at MTNR1b is replicable across ethnic groups, although ethnic diversity in the pattern and strength of linkage disequilibrium exists. [PMID 19937311]
• Genetic variation in this protein may contribute to abnormal glucose metabolism and related metabolic disturbances among Indian Asians. [PMID 19651812]
• Observational study and genome-wide association study of gene-disease association. (HuGE Navigator) [PMID 19651812]
• No significant differences were found in the hMel-1B and RORa receptors in patients with adolescent idiopathic scoliosis compared with controls [PMID 20733416]
• G-allele increases risk of type 2 diabetes and associates with estimates of beta-cell dysfunction and hepatic insulin resistance. [PMID 19324940]
• Observational study of gene-disease association and gene-environment interaction. (HuGE Navigator) [PMID 20802253]
• Genetic variation of MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity. [PMID 19455304]
• MTNR1B contributes to the phenotypic expression of polycystic ovary syndrome. [PMID 20207350]
• Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced beta-cell function, as indicated by homeostasis model assessment of beta-cell function. [PMID 21515849]
• Common variants of MTNR1B, G6PC2 and GCK are associated with elevated FPG and impaired insulin secretion, both individually and jointly, suggesting that these risk alleles may precipitate or perpetuate hyperglycemia in predisposed individuals. [PMID 20628598]
• Observational study and meta-analysis of gene-disease association. (HuGE Navigator) [PMID 20628598]
• Truncation of the C-terminal tail of both receptors (MT(1)Y7.64 and MT(2)Y7.64) inhibited internalization as well as the cAMP response, suggesting the importance of the C-terminal tail in these receptor functions. [PMID 18341518]
• The rs3781637 A/G polymorphism of the MTNR1B gene is associated with type 2 diabetes, plasma, total cholesterol and LDL-C levels in the Han Chinese population. [PMID 21470412]
• SNPs within the MTNR1B gene are associated with polycystic ovary syndrome in Han Chinese women. [PMID 20959387]
• Melatonin inhibited ERalpha mRNA expression & enhanced induction of pancreatic spasmolytic polypeptide in MT(1)-transfected breast cancer cells, suggesting a role for the MT(1) receptor in melatonin-regulated growth-suppression & gene-modulation. [PMID 12088876]
• The results demonstrate a down-regulation of melatonin receptors in regions affected by Parkinson disease, suggesting their possible involvement in the disease process. [PMID 20110911]
• Data suggest that the genetic effect of promoter polymorphisms of BMP4, IL6, leptin, MMP3, and MTNR1B can be synergistic for susceptibility to AIS. [PMID 21228692]
• MTNR1B variations associate with with increased body mass and decreased fasting blood glucose in Europeans. [PMID 20200315]
• Observational study of gene-disease association and gene-gene interaction. (HuGE Navigator) [PMID 19808892]
• This study confirms the association of gestational diabetes mellitus with the rs10830963 variant in a sample of the Greek population. [PMID 22450346]
• we concluded that MTNR1B SNP is not associated with either adolescent idiopathic scoliosis predisposition or curve severity in Japanese. [PMID 21308753]
• Common genetic variation within MTNR1B determines glucose-stimulated insulin secretion and plasma glucose concentrations. [PMID 19088850]
• The common variant in MTNR1B confers the risk of Type 2 diabetes and modulates FPG in both the Han Chinese and European populations. [PMID 20536959]
• MT(2) was localized to ganglion and bipolar cells in the inner nuclear layer, and to the inner segments of the photoreceptor cells, cellular processes in inner and outer plexiform layers . In AD patients intensity of MT(2)-staining was decreased. [PMID 17316165]
• Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer (melatonin receptor 2) [PMID 11940583]
• MT2 receptor interacts with melatonin. [PMID 15266022]
• MT1 receptor heterodimerizes with MT2 receptor. [PMID 15266022]
• MT2 receptor homodimerizes with itself. [PMID 15266022]
• This is the first single study, replicating the association between the MTNR1B locus and diabetes-related traits in overweight and obese children and adolescents. [PMID 21059861]
• Observational study of gene-disease association. (HuGE Navigator) [PMID 21059861]

PubMed Articles

Recent articles:

• Rasmussen-Torvik LJ et al. “Fasting glucose GWAS candidate region analysis across ethnic groups in the Multiethnic Study of Atherosclerosis (MESA).” Genet Epidemiol. 2012 May;36(4):384-91. PMID 22508271
• Deming SL et al. “Melatonin pathway genes and breast cancer risk among Chinese women.” Breast Cancer Res Treat. 2012 Apr;132(2):693-9. PMID 22138747
• Kristiansson K et al. “Genome-wide screen for metabolic syndrome susceptibility Loci reveals strong lipid gene contribution but no evidence for common genetic basis for clustering of metabolic syndrome traits.” Circ Cardiovasc Genet. 2012 Apr 1;5(2):242-9. PMID 22399527
• Vlassi M et al. “The rs10830963 variant of melatonin receptor MTNR1B is associated with increased risk for gestational diabetes mellitus in a Greek population.” Hormones (Athens). 2012 Jan-Mar;11(1):70-6. PMID 22450346
• Kwak SH et al. “A genome-wide association study of gestational diabetes mellitus in Korean women.” Diabetes. 2012 Feb;61(2):531-41. PMID 22233651
• Kettunen J et al. “Genome-wide association study identifies multiple loci influencing human serum metabolite levels.” Nat Genet. 2012 Jan 29;44(3):269-76. PMID 22286219
• Bonnefond A et al. “Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes.” Nat Genet. 2012 Jan 29;44(3):297-301. PMID 22286214
• Wang Y et al. “Association of six single nucleotide polymorphisms with gestational diabetes mellitus in a Chinese population.” PLoS One. 2011;6(11):e26953. PMID 22096510
• Kim YJ et al. “Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits.” Nat Genet. 2011 Sep 11;43(10):990-5. PMID 21909109
• Song JY et al. “Association of the rs10830963 polymorphism in MTNR1B with fasting glucose levels in Chinese children and adolescents.” Obes Facts. 2011;4(3):197-203. PMID 21701235

Top Pubmed articles linked to gene MTNR1B matching any search term:

• Peter I et al. “Association of Type 2 Diabetes Susceptibility Loci With One-Year Weight Loss in the Look AHEAD Clinical Trial.” Obesity (Silver Spring). 2012 Aug;20(8):1675-82. PMID 22307069
• Liao S et al. “Association of Genetic Variants of Melatonin Receptor 1B with Gestational Plasma Glucose Level and Risk of Glucose Intolerance in Pregnant Chinese Women.” PLoS One. 2012;7(7):e40113. PMID 22768333
• Linder K et al. “Allele summation of diabetes risk genes predicts impaired glucose tolerance in female and obese individuals.” PLoS One. 2012;7(6):e38224. PMID 22768041
• Hotta K et al. “Association between type 2 diabetes genetic susceptibility loci and visceral and subcutaneous fat area as determined by computed tomography.” J Hum Genet. 2012 May;57(5):305-10. PMID 22377712
• Rasmussen-Torvik LJ et al. “Fasting glucose GWAS candidate region analysis across ethnic groups in the Multiethnic Study of Atherosclerosis (MESA).” Genet Epidemiol. 2012 May;36(4):384-91. PMID 22508271
• Grimsby JL et al. “Race-ethnic differences in the association of genetic loci with HbA1c levels and mortality in U.S. adults: the third National Health and Nutrition Examination Survey (NHANES III).” BMC Med Genet. 2012 Apr 27;13(1):30. PMID 22540250
• Winkler C et al. “Lack of association of type 2 diabetes susceptibility genotypes and body weight on the development of islet autoimmunity and type 1 diabetes.” PLoS One. 2012;7(4):e35410. PMID 22558147
• Deming SL et al. “Melatonin pathway genes and breast cancer risk among Chinese women.” Breast Cancer Res Treat. 2012 Apr;132(2):693-9. PMID 22138747
• Vlassi M et al. “The rs10830963 variant of melatonin receptor MTNR1B is associated with increased risk for gestational diabetes mellitus in a Greek population.” Hormones (Athens). 2012 Jan-Mar;11(1):70-6. PMID 22450346
• Kwak SH et al. “A genome-wide association study of gestational diabetes mellitus in Korean women.” Diabetes. 2012 Feb;61(2):531-41. PMID 22233651
• Bonnefond A et al. “Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes.” Nat Genet. 2012 Jan 29;44(3):297-301. PMID 22286214
• Kim YJ et al. “Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits.” Nat Genet. 2011 Sep 11;43(10):990-5. PMID 21909109
• Takahashi Y et al. “Lack of association between adolescent idiopathic scoliosis and previously reported single nucleotide polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a Japanese population.” J Orthop Res. 2011 Jul;29(7):1055-8. PMID 21308753
• Song JY et al. “Association of the rs10830963 polymorphism in MTNR1B with fasting glucose levels in Chinese children and adolescents.” Obes Facts. 2011;4(3):197-203. PMID 21701235
• Reinehr T et al. “Relationship between MTNR1B (melatonin receptor 1B gene) polymorphism rs10830963 and glucose levels in overweight children and adolescents.” Pediatr Diabetes. 2011 Jun;12(4 Pt 2):435-41. PMID 21366812
• Holzapfel C et al. “Association of a MTNR1B gene variant with fasting glucose and HOMA-B in children and adolescents with high BMI-SDS.” Eur J Endocrinol. 2011 Feb;164(2):205-12. PMID 21059861
• de Miguel-Yanes JM et al. “Genetic risk reclassification for type 2 diabetes by age below or above 50 years using 40 type 2 diabetes risk single nucleotide polymorphisms.” Diabetes Care. 2011 Jan;34(1):121-5. PMID 20889853
• Soranzo N et al. “Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.” Diabetes. 2010 Dec;59(12):3229-39. PMID 20858683