Search

Polycystic ovarian syndrome (PCOS) is a genetically complex disorder that involves the interplay of multiple genes and environmental factors. It is characterized by anovulation and irregular menses and is associated with type 2 diabetes. Neuroendocrine pathways and ovarian and adrenal dysfunctions are possibly implicated in the disorder pathogenesis. The melatonin system plays a role in PCOS. Melatonin receptors are expressed on the surface of ovarian granulosa cells, and variations in the melatonin receptor genes have been associated with increased risk of PCOS in both familial and sporadic cases. We have recently reported the association of variants in MTNR1A and MTNR1B genes with familial type 2 diabetes. In this study, we aimed to investigate whether MTNR1A and MTNR1B contribute to PCOS risk in peninsular families. In 212 Italian families phenotyped for PCOS, we amplified by microarray 14 variants in the MTNR1A gene and 6 variants in the MTNR1B gene and tested them for linkage and linkage disequilibrium with PCOS. We detected 4 variants in the MTNR1A gene and 2 variants in the MTNR1B gene significantly linked and/or in linkage disequilibrium with the risk of PCOS (P < 0.05). All variants are novel and have not been reported before with PCOS or any of its related phenotypes, except for 3 variants previously reported by us to confer risk for type 2 diabetes and 1 variant for type 2 diabetes-depression comorbidity. These findings implicate novel melatonin receptor genes' variants in the risk of PCOS with potential functional roles. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Melatonin regulates the mammalian circadian rhythm and plays metabolic functions such as glucose homeostasis. Both melatonin receptors (MTNR1A and MTNR1B, encoded by the MTNR1A and MTNR1B genes, respectively) are expressed in pancreatic beta cells and mediate the glucometabolic roles of melatonin as well as insulin secretion. The MTNR1B gene is a well-known genetic risk factor in type 2 diabetes (T2D); however, little is known about the involvement of the MTNR1A gene in here T2D. We aimed to investigate whether MTNR1A is linked to and/or associated with familial T2D. SUBJECTS AND METHODS: We genotyped 14 single nucleotide polymorphisms within the MTNR1A gene in 212 peninsular Italian families with T2D. We performed parametric linkage and linkage disequilibrium analyses to investigate the role of MTNR1A variants in conferring T2D risk. We considered variants statistically significant if conferring linkage or linkage disequilibrium with p < 0.05. RESULTS: We found 3 novel variants (rs62350392, rs2119883, and rs13147179) significantly linked to and/or associated with T2D in multigenerational Italian families. CONCLUSIONS: This is the first study to report MTNR1A as a novel risk gene in T2D. Functional studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Primary brain tumors remain among the deadliest of all cancers. Glioma grade IV (glioblastoma), the most common and malignant type of brain cancer, is associated with a 5-year survival rate of < 5%. Melatonin has been widely reported as an anticancer molecule, and we have recently demonstrated that the ability of gliomas to synthesize and accumulate this indolamine in the surrounding microenvironment negatively correlates with tumor malignancy. However, our understanding of the specific effects mediated through the activation of melatonin membrane receptors remains limited. Thus, here we investigated the specific roles of MT1 and MT2 in gliomas and medulloblastomas. Using the MT2 antagonist DH97, we showed that MT1 activation has a negative impact on the proliferation of human glioma and medulloblastoma cell lines, while MT2 activation has an opposite effect. Accordingly, gliomas have a decreased mRNA expression of MT1 (also known as MTNR1A) and an increased mRNA expression of MT2 (also known as MTNR1B) compared to the normal brain cortex. The MT1/MT2 expression ratio negatively correlates with the expression of cell cycle-related genes and is a positive prognostic factor in gliomas. Notably, we showed that functional selective drugs that simultaneously activate MT1 and inhibit MT2 exert robust anti-tumor effects in vitro and in vivo, downregulating the expression of cell cycle and energy metabolism genes in glioma stem-like cells. Overall, we provided the first evidence regarding the differential roles of MT1 and MT2 in brain tumor progression, highlighting their relevance as druggable targets. Key messages: • MT1 impairs while MT2 promotes the proliferation of glioma and medulloblastoma cell lines. • Gliomas have a decreased expression of MT1 and an increased expression of MT2 compared to normal brain cortex. • Tumors with a high MT1/MT2 expression ratio have significantly better survival rates. • Functional selective drugs that simultaneously activate MT1 and inhibit MT2 downregulate the expression of cell cycle and energy metabolism genes in glioma stem-like cells and exert robust anti-tumor effects in vivo. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a condition in which a woman's levels of the sex hormones (estrogen and progesterone) are out of balance, leading to the growth of ovarian cysts. PCOS can affect the menstrual cycle, fertility, cardiac function and even appearance of women. Therefore, we aimed to explore the genetic polymorphism of the melatonin receptors 1A and 1B in obese patients with PCOS to identify a new theoretical basis for its treatment. Patients presenting with PCOS (n=359) were enrolled and classified into an obese OB-PCOS group [body mass index (BMI) of PCOS patients ≥25 kg/m2] or a nonobese NOB-PCOS group, and 215 oviduct infertile patients who experienced normal ovulation were used as the control group. All baseline characteristics, endocrine hormone levels, lipid and glucose metabolism, and insulin indices were measured. The genotypes of rs2119882 within the MTNR1A gene and of rs10830963 within the MTNR1B gene were determined by PCR-RFLP; the genotype frequency and the difference in the distribution of allele frequency were compared. For rs2119882, C allele carriers who were not diagnosed with PCOS had an increased risk of developing PCOS, and C allele carriers with PCOS had an increased risk of developing OB-PCOS. For rs10830963, G allele carriers who were not diagnosed with PCOS had an increased risk of developing PCOS. The TT genotype in rs2119882 and the CC genotype in rs10830963 were protective factors for OB-PCOS, and increased levels of LH, testosterone, and estradiol and abnormal menstruation were key risk factors for PCOS. Furthermore, the TT genotype at the rs2119882 site was the key protective factor for OB-PCOS patients. Our study found that MTNR1A rs2119882 and MTNR1B rs10830963 could increase the risk for PCOS and cause glycolipid metabolism disorder in PCOS patients. [ABSTRACT FROM AUTHOR]

The melatonin receptors are G protein-coupled receptors (GPCR) that bind melatonin. Three types of melatonin receptors have been cloned. The MTNR1A (or Mel1A or MT1) and MTNR1B (or Mel1B or MT2) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MTNR1C (or Mel1C or MT3) has been identified in amphibians and birds. Previous research has shown that the three common melatonin receptors regulate physiological processes, including seasonal reproduction and ovarian physiology. However, whether or not any polymorphisms of the different melatonin receptor subtypes are associated with reproductive traits in chickens is not known. In this study, we performed candidate gene analysis to identify single-nucleotide polymorphisms (SNPs) in the MTNR1A, MTNR1B, and MTNR1C genes in the Erlang Mountain Chicken population. SNP discovery was achieved by sequencing pooled DNA samples. Direct PCR-sequencing, PCR-SSCP/PCR-sequencing, and PCR-RFLP method were used to genotype the MTNR1A, MTNR1B, and MTNR1C genes, respectively. The GLM Procedure was used to estimate the statistical significance of association between genotypes at each locus and reproductive traits of chickens. In a sample of 460 chickens, four novel polymorphisms (JQ249890:g.384T>C, JQ249891:g.387T>C, JQ249894:g.63C>T, and JQ249896:g.294G>A) were detected in the melatonin receptor genes MTNR1A, MTNR1B, and MTNR1C, respectively. A statistically significant association (P < 0.01) was found between two SNPs (MTNR1A SNP, MTNR1C SNP) and reproductive traits: egg number at 300 days of age (EN) and age at first egg (AFE).

Background/Aims: The purpose of this study was to investigate the association between MTNR1A and MTNR1B gene polymorphisms and gestational diabetes mellitus (GDM) in Han Chinese women. Methods: Study participants included 350 patients with GDM and 480 control subjects. Three single-nucleotide polymorphisms (SNPs; rs2119882 in MTNR1A and rs10830963 and rs10830962 in MTNR1B) were genotyped using direct sequencing. Genotype and allele distributions of SNPs in cases of GDM and controls were analyzed. Association of the MTNR1A and MTNR1B gene variants with plasma glucose and insulin levels as well as blood lipid levels was further investigated. Results: The frequencies of genotypes and allele types of rs2119882 in MTNR1A and rs10830963 in MTNR1B were significantly different between women with GDM and controls (p < 0.05). Moreover, in the GDM group, these SNPs were associated with increased fasting plasma glucose concentrations (p < 0.001) and increased homeostasis model assessment of insulin resistance (p < 0.001). The rs10830962 polymorphism in MTNR1B was not associated with an increased risk of developing GDM or any of the clinical or metabolic characteristics in patients with GDM (p > 0.05). Conclusion: The genetic polymorphisms rs2119882 in MTNR1A and rs10830963 in MTNR1B are associated with an increased risk of developing GDM and insulin resistance in Han Chinese women. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives. Antipsychotics-induced tardive dyskinesia (TD) has been suggested to be related to altered dopaminergic neurotransmission in the striatum. Melatonin has a modulating effect on dopaminergic neurotransmission in the brain; therefore, the hypothesis of an association between the melatonin receptor genes ( MTNR1A, MTNR1B) and antipsychotics-induced TD was examined in this study. Methods. Schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale, and only patients who were either free of any abnormal involuntary movement (non-TD group) or who demonstrated persistent TD (TD group) were enrolled. Genotyping of six tagging single nucleus polymorphisms (SNPs) in the melatonin receptor genes ( MRNR1A, MTNR1B) was then performed for each subject. Results. Four hundred and eighteen inpatients (TD==256, non-TD==162) fitted the study criteria and underwent TD assessment and genotyping. Individual haplotype analysis showed that the haplotype ATG was significantly associated with non-TD (permutation P==0.037), and the association was also found to be significant by global haplotype analyses (permutation P==0.045). Conclusions. Our results indicated a significant association between the haplotype ATG in the MTNR1A gene and non-TD. Further replication in other countries or other populations is indicated. [ABSTRACT FROM AUTHOR]