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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]

Sheep are a valuable livestock species worldwide, providing meat, milk, and various dairy products. This article aims to review the latest literature on the melatonin receptor 1A (MTNR1A) gene as a potential candidate gene associated with reproductive traits, particularly the litter size trait in sheep, by searching various databases for available literature. Studies have shown that different parts of the MTNR1A gene play various roles in sheep. By identifying marker genes associated with reproductive traits in MTNR1A polymorphisms linked to the litter size trait, breeders can achieve a faster selection response in sheep breeding by recognizing the genomic region where these genes are located and understanding their physiological functions. Therefore, highlighting the literature on these functions and their association with reproductive traits may contribute to improving the genetic makeup during sheep breeding.

Sheep are a valuable livestock species worldwide, providing meat, milk, and various dairy products. This article aims to review the latest literature on the melatonin receptor 1A (MTNR1A) gene as a potential candidate gene associated with reproductive traits, particularly the litter size trait in sheep, by searching various databases for available literature. Studies have shown that different parts of the MTNR1A gene play various roles in sheep. By identifying marker genes associated with reproductive traits in MTNR1A polymorphisms linked to the litter size trait, breeders can achieve a faster selection response in sheep breeding by recognizing the genomic region where these genes are located and understanding their physiological functions. Therefore, highlighting the literature on these functions and their association with reproductive traits may contribute to improving the genetic makeup during sheep breeding.

Aim: This study aimed to investigate whether single‐nucleotide polymorphisms (SNPs) in the genes encoding 5‐HTR2A (5‐Hydroxytryptamine (serotonin) receptor 2A) and MTNR1A (melatonin receptor 1A) may contribute to postoperative pain perception after root canal treatment. We hypothesised that SNPs in HTR2A and MTNR1A genes were associated with postoperative pain after root canal treatment. Methodology: This genetic cohort study enrolled patients with single‐rooted teeth diagnosed with pulp necrosis and asymptomatic apical periodontitis before root canal treatment. Root canal treatment was performed in one session using a standardized protocol. Postoperative pain and tenderness were assessed using a visual analogue scale (recorded every day for 7 days and on the 14th and 30th days after root canal treatment). Genomic DNA was extracted from saliva and used to genotype the SNPs in HTR2A (rs4941573 and rs6313) and MTNR1A (rs6553010, rs6847693 and rs13140012) using real‐time polymerase chain reaction. Genotypes were compared using univariate and multivariate Poisson regression with generalized estimating equations (p <.05). Results: In total, 108 patients were enrolled in this study. The SNPs rs6553010 (MTNR1A), rs4941573 and rs6313 (HTR2A) were associated with an increased risk of developing pain after root canal treatment (p <.05). Conclusions: This study suggests that SNPs in HTR2A and MTNR1A influence pain response after root canal treatment. [ABSTRACT FROM AUTHOR]

Sheep are a valuable livestock species worldwide, providing meat, milk, and various dairy products. This article aims to review the latest literature on the melatonin receptor 1A (MTNR1A) gene as a potential candidate gene associated with reproductive traits, particularly the litter size trait in sheep, by searching various databases for available literature. Studies have shown that different parts of the MTNR1A gene play various roles in sheep. By identifying marker genes associated with reproductive traits in MTNR1A polymorphisms linked to the litter size trait, breeders can achieve a faster selection response in sheep breeding by recognizing the genomic region where these genes are located and understanding their physiological functions. Therefore, highlighting the literature on these functions and their association with reproductive traits may contribute to improving the genetic makeup during sheep breeding.

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]

Simple Summary: The aim of this research was to study the effect of MTNR1A gene polymorphisms on the reproductive performance of two Mediterranean sheep breeds. A total of 26 SNPs were found, and three SNPs caused amino acid changes. Two SNPs were totally linked and correlated with reproductive activity resumption. This study consists of a piece of new useful knowledge for the control of sheep reproductive seasonality and farm management that could improve genetic selection, especially in countries where agriculture relies mainly on sheep farming. Sheep farming plays an important economic role, and it contributes to the livelihoods of many rural poor in several regions worldwide and particularly in Tunisia. Therefore, the steady improvement of ewes' reproductive performance is a pressing need. The MTNR1A gene has been identified as an important candidate gene that plays a key role in sheep reproduction and its sexual inactivity. It is involved in the control of photoperiod-induced seasonality mediated by melatonin secretion. The aim of this study was to identify SNPs in the MTNR1A gene in two Tunisian breeds, Barbarine (B) and Queue Fine de l'Ouest (QFO). DNA extracted from the blood of 77 adult ewes was sequenced. Selected ewes were exposed to adult fertile rams. A total of 26 SNPs were detected; 15 SNPs in the promoter region and 11 SNPs in the exon II were observed in both (B) and (QFO) breeds. The SNP rs602330706 in exon II is a novel SNP detected for the first time only in the (B) breed. The SNPs rs430181568 and rs40738822721 (SNP18 and SNP20 in our study, respectively) were totally linked in this study and can be considered a single marker. DTL was associated with SNP18 and SNP20 in (B) ewes (p < 0.05); however, no significant difference was detected between the three genotypes (G/G, G/A, and A/A) at these two SNPs. Fertility rate and litter size parameters were not affected by SNP18 and SNP20. There was an association between these two polymorphisms and (B) lambs' birth weights (p < 0.05). Furthermore, the ewes with the A/A genotype gave birth to lambs with a higher weight compared to the other two genotypes for this breed (p < 0.05). There was not an association between SNP 18 and SNP20 and (QFO) ewes' reproductive parameters. These results might be considered in future sheep selection programs for reproductive genetic improvement. [ABSTRACT FROM AUTHOR]

Background and purpose: Melatonin is a well-known neuroendocrine reproductive hormone-based hormone that has an important role in the circadian clock system and has potent antioxidant properties. New studies have also suggested an antitumor role for melatonin. The role of melatonin receptors is proven in many cancers, including colon and breast cancers, but so far, no study has been performed in children with leukemia. To the best of our knowledge, this is the first study to investigate MT1A receptor polymorphism in children with leukemia using RELP-PCR. Materials and methods: In this case-control study, 84 patients and 70 healthy individuals were included. After informed consent had been obtained, 10 ml of peripheral blood were taken from the participants. Genomic DNA was extracted using salting-out method and PCR-RFLP was used to evaluate the frequency of allelic and genotypic polymorphisms. Results: The genotypes of MT1 gene rs2119882 polymorphism in control group included 40% TT genotype, 50% TC genotype, and 10% CC genotype. In patients, 40% had TT genotype, 35% had TC genotype, and 25% had CC genotype. Chi-square test showed a significant difference in genotypes between the groups studied (P

Background: Sleep disorder, frequently observed among perimenopausal women, decreases quality of life. Melatonin is reported to ameliorate circadian imbalances and thus can be employed as a treatment for perimenopausal sleep disorder patients. We attempted to clarify whether and how melatonin affects perimenopausal sleep disorders. Methods: Study patients consisted of 120 perimenopausal women divided into 3 groups: (i) perimenopausal women without sleep disorder (n = 60); (ii) those with sleep disorder but without melatonin treatment (n = 30); and (iii) those with sleep disorder with melatonin treatment (n = 30). During the period March 2019 to December 2019, the following data was collected and analyzed: Pittsburgh Sleep Quality index (PSQI) score, sex hormones, melatonin, melatonin 1A receptor (MTNR1A), protein kinase A (PKA), extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylation–PKA (p-PKA), and p-ERK1/2 levels. We compared these data between the groups. Results: Melatonin administration showed the following in female patients with postmenopausal sleep disorder: (1) significantly decreased the PSQI scores, (2) up-regulated melatonin levels and MTNR1A protein expression, (3) promoted the phosphorylation pathway of the PKA-ERK1/2 pathway in peripheral blood, and (4) significantly improved follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) levels. Melatonin administration had no significant effect on progesterone (P), testosterone (T) or prolactin (PRL). Conclusions: Melatonin therapy alleviated perimenopausal sleep disorders. Up-regulation of MTNR1A expression and improvement of the hormone balance were also observed, which may the reason for the observed sleep-disorder-amelioration. Melatonin has the potential to be a useful option for perimenopausal sleep disorders.

Sheep farming plays an important economic role, and it contributes to the livelihoods of many rural poor in several regions worldwide and particularly in Tunisia. Therefore, the steady improvement of ewes’ reproductive performance is a pressing need. The MTNR1A gene has been identified as an important candidate gene that plays a key role in sheep reproduction and its sexual inactivity. It is involved in the control of photoperiod-induced seasonality mediated by melatonin secretion. The aim of this study was to identify SNPs in the MTNR1A gene in two Tunisian breeds, Barbarine (B) and Queue Fine de l’Ouest (QFO). DNA extracted from the blood of 77 adult ewes was sequenced. Selected ewes were exposed to adult fertile rams. A total of 26 SNPs were detected; 15 SNPs in the promoter region and 11 SNPs in the exon II were observed in both (B) and (QFO) breeds. The SNP rs602330706 in exon II is a novel SNP detected for the first time only in the (B) breed. The SNPs rs430181568 and rs40738822721 (SNP18 and SNP20 in our study, respectively) were totally linked in this study and can be considered a single marker. DTL was associated with SNP18 and SNP20 in (B) ewes (p < 0.05); however, no significant difference was detected between the three genotypes (G/G, G/A, and A/A) at these two SNPs. Fertility rate and litter size parameters were not affected by SNP18 and SNP20. There was an association between these two polymorphisms and (B) lambs’ birth weights (p < 0.05). Furthermore, the ewes with the A/A genotype gave birth to lambs with a higher weight compared to the other two genotypes for this breed (p < 0.05). There was not an association between SNP 18 and SNP20 and (QFO) ewes’ reproductive parameters. These results might be considered in future sheep selection programs for reproductive genetic improvement.

Background and purpose: Melatonin is a well-known neuroendocrine reproductive hormonebased hormone that has an important role in the circadian clock system and has potent antioxidant properties. New studies have also suggested an antitumor role for melatonin. The role of melatonin receptors is proven in many cancers, including colon and breast cancers, but so far, no study has been performed in children with leukemia. To the best of our knowledge, this is the first study to investigate MT1A receptor polymorphism in children with leukemia using RELP-PCR. Materials and methods: In this case-control study, 84 patients and 70 healthy individuals were included. After informed consent had been obtained, 10 ml of peripheral blood were taken from the participants. Genomic DNA was extracted using salting-out method and PCR-RFLP was used to evaluate the frequency of allelic and genotypic polymorphisms. Results: The genotypes of MT1 gene rs2119882 polymorphism in control group included 40% TT genotype, 50% TC genotype, and 10% CC genotype. In patients, 40% had TT genotype, 35% had TC genotype, and 25% had CC genotype. Chi-square test showed a significant difference in genotypes between the groups studied (P<0.05). Conclusion: This study confirmed the association between MT1 gene rs2119882 polymorphism and increased risk of childhood leukemia, Therefore, screening for melatonin receptor polymorphism can be helpful in prognosis and prevention of disease and appropriate treatment strategies in this cancer. [ABSTRACT FROM AUTHOR]

Objective: The primary objective is to identify and characterize the Single Nucleotide Polymorphisms (SNPs) within the MTNR1A gene sequence in thin-tailed Indonesian ewes to assess the possible association of MTNR1A gene polymorphism with litter size trait., Methods: Forty-seven thin-tailed Indonesian sheep were selected for the study. Genotyping involved collecting blood samples, and sequencing exon 2 of the MTNR1A gene., Results: The study identified 19 novel SNPs, with 10 being non-synonymous variations, in the MTNR1A gene of Thin-tailed Indonesian ewes. One non-synonymous SNP (rs1087815963) showed a significant association with litter size, with the GC genotype exhibiting a higher average litter size than the GG genotype. The deleterious impact of p.Val127Ile SNP was predicted by various in silico tools that predicted a highly damaging effect of p.Val127Ile SNP on the structure, function, and stability of MTNR1A. Docking reactions showed a critical involvement of this locus with the binding with melatonin., Conclusion: In conclusion, the results of our study suggest that rs1087815963 has a remarkable negative impact on the MTNR1A with a putative alteration in the binding with melatonin. Therefore, it can be stated that the implementation of the novel p.Val127Ile could be a useful marker in marker-assisted selection.

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]

Summary: Melatonin is a circadian regulatory hormone with neuroprotective properties. We have previously demonstrated the association of the genetic variant rs12506228 near the melatonin receptor 1A gene (MTNR1A) with intolerance to shift‐work. Furthermore, this variant has been connected to Alzheimer's disease. Because of the previously suggested role of melatonin signalling in foetal neurocognitive and sleep development, we studied here the association of rs12506228 with early development. The study sample comprised 8‐month‐old infants from the Finnish CHILD‐SLEEP birth cohort (n = 1,301). Parental questionnaires assessed socioemotional, communication and motor development, as well as sleep length and night awakenings. The A allele of rs12506228 showed an association with slower socioemotional (p =.025) and communication (p =.0098) development, but no direct association with sleep. However, the association of the Finnish seasons with infant sleep length interacted with rs12506228. Taken together, rs12506228 near MTNR1A, which has been previously linked to adult and elderly traits, is shown here to associate with slower early cognitive development. In addition, these results suggest that the darker seasons associate with longer infant sleep time, but only in the absence of the rs12506228 AA genotype. Because the risk allele has been connected to fewer brain MT1 melatonin receptors, these associations may reflect the influence of decreased melatonin signalling in early development. [ABSTRACT FROM AUTHOR]

The water buffalo is a fundamental resource, especially in developing countries, however, differently from other species, its genetic potential is still poorly investigated. In this work, we performed a candidate gene association study for milk composition in 491 female buffaloes. Animals were from four farms located in Southern Italy, where the Out-of-Breeding-Season-Mating technique is usually performed. We analysed three genes: (1) the signal transducer and activator of transcription 5A (STAT5A), (2) the tumour necrosis factor alpha (TNFα) and (3) the melatonin receptor 1A (MTNR1A). We confirmed the mutation at the MTNR1A gene and we found five novel single nucleotide polymorphisms (SNPs): one in the TNFα and four in the STAT5A. No associations were found for the SNPs in the MTNR1A and TNFα genes, while we identified a marked association with milk protein % for a C > T substitution at the STAT5A gene. At this locus, the TT buffaloes showed significantly higher protein percentage in milk. Conversely, this genotype class was the less frequent in the population. Moreover, an A > G substitution at the STAT5A showed an influence on reproductive seasonality, with the advantageous allele most frequent in the population, suggesting a possible effect of selection for this trait. The C > T substitution on STAT5A detected in present study could be used in marker assisted selection of Mediterranean Italian buffalo, and should be monitored to understand the reasons behind the low frequency of the favourable genotype at this locus and to stop this unfavourable trend in the population.

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 aim of this study was to characterize and identify causative SNPs in the MTNR1A gene responsible for the reproductive seasonality traits in the Rasa aragonesa sheep breed. A total of 290 ewes (155, 84 and 51 mature, young and ewe lambs, respectively) from one flock were controlled from January to August. The following three reproductive seasonality traits were considered: the total days of anoestrus (TDA) and the progesterone cycling months (P4CM); both ovarian function seasonality traits based on blood progesterone levels; and the oestrus cycling months (OCM) based on oestrous detection, which indicate behavioural signs of oestrous. We have sequenced the total coding region plus 733 and 251 bp from the promoter and 3′-UTR regions, respectively, from the gene in 268 ewes. We found 9 and 4 SNPs associated with seasonality traits in the promoter (for TDA and P4CM) and exon 2 (for the three traits), respectively. The SNPs located in the gene promoter modify the putative binding sites for various trans -acting factors. In exon 2, two synonymous SNPs affect RFLP sites, rs406779174/ Rsa I (for the three traits) and rs430181568/ Mnl I (for OCM), and they have been related with seasonal reproductive activity in previous association studies with other breeds. SNP rs400830807, which is located in the 3′-UTR, was associated with the three traits, but this did not modify the putative target sites for ovine miRNAs according to in silico predictions. Finally, the SNP rs403212791 ( NW_014639035.1 : g.15099004G > A), which is also associated with the three seasonality phenotypes, was the most significant SNP detected in this study and was a non-synonymous polymorphism, leading a change from an Arginine to a Cysteine (R336C). Haplotype analyses confirmed the association results and showed that the effects found for the seasonality traits were caused by the SNPs located in exon 2. We have demonstrated that the T allele in the SNP rs403212791 in the MNTR1A gene is associated with a lower TDA and higher P4CM and OCM values in the Rasa Aragonesa breed. [ABSTRACT FROM AUTHOR]

The water buffalo is a fundamental resource, especially in developing countries, however, differently from other species, its genetic potential is still poorly investigated. In this work, we performed a candidate gene association study for milk composition in 491 female buffaloes. Animals were from four farms located in Southern Italy, where the Out-of-Breeding-Season-Mating technique is usually performed. We analysed three genes: (1) the signal transducer and activator of transcription 5A (STAT5A), (2) the tumour necrosis factor alpha (TNFα) and (3) the melatonin receptor 1A (MTNR1A). We confirmed the mutation at theMTNR1Agene and we found five novel single nucleotide polymorphisms (SNPs): one in theTNFαand four in theSTAT5A. No associations were found for the SNPs in theMTNR1AandTNFαgenes, while we identified a marked association with milk protein % for a C > T substitution at theSTAT5Agene. At thislocus, the TT buffaloes showed significantly higher protein percentage in milk. Conversely, this genotype class was the less frequent in the population. Moreover, an A > G substitution at theSTAT5Ashowed an influence on reproductive seasonality, with the advantageous allele most frequent in the population, suggesting a possible effect of selection for this trait. The C > T substitution onSTAT5Adetected in present study could be used in marker assisted selection of Mediterranean Italian buffalo, and should be monitored to understand the reasons behind the low frequency of the favourable genotype at thislocusand to stop this unfavourable trend in the population. [ABSTRACT FROM PUBLISHER]

Melatonin is a hormone with complex roles in the pathogenesis of autoimmune disorders. Over the years, it has become clear that melatonin may exacerbate some autoimmune conditions, whereas it alleviates others such as multiple sclerosis. Multiple sclerosis is an autoimmune disorder characterized by a dysregulated immune response directed against the central nervous system. Indeed, the balance between pathogenic CD4+ T cells secreting IFN-γ (TH1) or IL-17 (TH17); and FoxP3+ regulatory T cells and IL-10+ type 1 regulatory T cells (Tr1 cells) is thought to play an important role in disease activity. Recent evidence suggests that melatonin ameliorates multiple sclerosis by controlling the balance between effector and regulatory cells, suggesting that melatonin-triggered signaling pathways are potential targets for therapeutic intervention. Here, we review the available data on the effects of melatonin on immune processes relevant for MS and discuss its therapeutic potential. [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).

Melatonin receptors, which mediate the functions of melatonin, play an important role in adipocyte differentiation, energy, and lipid metabolism. The aim of this study was to identify single nucleotide polymorphisms (SNPs) in bovine melatonin receptor 1A (MTNR1A) and to determine if these SNPs are associated with body measurement traits (BMTs) and meat quality traits (MQTs) in Qinchuan cattle. We identified three synonymous mutations (A455G, A497G, and C635T) and one missense mutation (G489A) p.Asp224Asn in MTNR1A gene in 420 Qinchuan cattle by sequencing. Association analysis indicated that these four SNPs were associated with some of the BMTs and MQTs (P < 0.05). Further, 6 combined haplotypes were constructed to guarantee the reliability of analysis results. Individuals with diplotypes H2H2 (AA-GG-GG-CC) had greater chest depth, heart girth, loin muscle area, and more back fat than the other combinations (P < 0.05). Pertaining to G489A mutation, RT-PCR study exhibited a higher mRNA expression of MTNR1A gene among individuals with SNP1/2/4-AG-GA-CT genotype than those with SNP1/2/4-AA-GG-CC genotype (P < 0.05). These results suggest that the genotype H2H2 could be used as a molecular marker of the combined genotype for future selection for BMTs and MQTs in Qinchuan cattle. [ABSTRACT FROM AUTHOR]

• The average secretion level of MT in Tibetan sheep blood was highest occurred during diestrus and the lowest during proestrus. In addition, the secretion level of MT at night was significantly higher than that at day. • This study found that MTNR1A was distributed in all tissues of HPGA during the estrous cycle in Tibetan sheep, and there were significant differences in the expression of MTNR1A in various tissues. • This study found that there were also significant differences in the expression of MTNR1A mRNA in HPGA during oestrus cycle in Tibetan sheep. • The differences in MT secretion pattern and the expression of MTNR1A in HPGA suggest that they may be affected by steroid hormone secretion during the estrous cycle of Tibetan sheep. The melatonin 1A receptor (MTNR1A) is a membrane receptor distributed across the mammalian gonadal axis-associated membrane. Melatonin (MT) can specifically bind with MTNR1A on the cell membrane and regulates mammalian reproductive activities. However, the role of MTNR1A in regulating the reproductive physiological activities of sheep in the Tibetan Plateau remains unclear. In this study, the MT content in Tibetan sheep blood during the estrous cycle was detected by ELISA. The distribution of MTNR1A in the hypothalamus-pituitary–gonadal axis (HPGA) was analyzed by immunohistochemistry and immunofluorescence. Western blot and qRT-PCR were used to detect dynamic changes of MTNR1A mRNA and protein expression, and the protein distributions in the HPGA. The results showed that the average secretion level of MT in Tibetan sheep blood was highest occurred during diestrus and the lowest during proestrus. Additionally, the secretion of MT at night was significantly higher than during the day. The immunopositive products of MTNR1A were primarily distributed around the glial cells in the dorsal hypothalamic nucleus region, chromophobe cells, and eosinophilic cytoplasm in the pituitary gland, follicular granular layer, follicular adventitia, tubal mucosa, cilia, endometrium, interstices, and glands in the uterus. The expression trends of MTNR1A mRNA and proteins in the HPGA during the estrous cycle were the same. The relative expression levels of MTNR1A mRNA and proteins in the hypothalamus and ovaries were the highest during proestrus and the lowest during metestrus; the highest during diestrus in the pituitary and oviducts; the highest during metestrus in the uterus. Collectively, the differences in the secretion of MT in Tibetan sheep blood and the expression of MTNR1A in HPGA suggest that they may be affected by steroid hormone secretion during the estrous cycle of Tibetan sheep, which has a potential impact on the regulation of animal estrous cycle. [ABSTRACT FROM AUTHOR]

The melatonin receptor 1A (MTNR1A) and inhibin alpha subunit (INHA) genes play a significant role in the reproductive characteristics of animals. Blood samples were collected from 371 goats (Honamli and Hair) reared in Antalya and Burdur. The polymerase chain reaction (PCR) products were digested by RsaI for the MTNR1A gene and HaeII for the INHA gene. Two alleles (A and G) and three genotypes (AA, AG, and GG) were observed for the INHA gene, while two alleles (R and r) and two genotypes (RR and Rr) were observed for the MTNR1A gene. The highest allelic frequency value for G (91.8%) was found in Honamli goat breeds for the INHA gene while the highest value for R (98.1%) was found in Hair goat breeds for the MTNR1A gene. The GG genotype for the INHA gene and the RR genotype for the MTNR1A gene were identified as the most common genotypes of the Honamli and Hair goat breeds. The rr genotype for the MTNR1A gene could not be determined in the breeds. Both Honamli and Hair goat breeds were in Hardy-Weinberg equilibrium for the genes that were studied. In conclusion, this study confirms the existence of genetic polymorphism in the MTNR1A and INHA genes as detected by PCR-RFLP analysis in Honamli and Hair goat breeds. [ABSTRACT FROM AUTHOR]

Melatonin regulates some major physiological processes such as maturation and function of reproductive system, pubertal development, seasonal reproduction and adaptation. The activation of melatonin hormone is mediated by melatonin receptor. Previous studies showed melatonin receptor 1A gene (MTNR1A) is highly polymorphic in seasonally breeding species. The aim of the present study was detection of MTNR1A polymorphism and its association with production (body weights at birth, 1, 3, 6, 9 and 12 month of age) and reproduction (litter size) traits in Zandi sheep using PCR-RFLP methodology. Hundred blood samples were randomly collected and genomic DNA was isolated using modified salting out method. A large fragment of exon 2 of MTNR1A gene was amplified by PCR using specific primer pairs. After amplification, the PCR product was digested with MnlI endonuclease. Restricted digestion allowed the determination of two alleles (M, m) and two genotypes (MM, Mm) with frequencies of 0.91, 0.09 and 0.82, 0.18, respectively. Least square means showed that MM individuals had higher body weight at one month of age (BW1) than Mm individuals (P<0.05). No associations were found between observed genotypes and other studied traits. In the subsequent studies using a large number of samples along with the other important parameters such as sire effect and the lamb health status which may influence lamb body weight is recommended. [ABSTRACT FROM AUTHOR]

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]

The aims of this study were 1) to investigate the effect of MTNR1A gene polymorphisms on reproductive performance in ewes of one Italian and two Slovenian dairy sheep breeds (Sarda, Istrian Premenka and Boska, respectively) which were located at different latitudes, and 2) to highlight if the different season of the male placement with females that was utilized in the different breeding systems in Sardinia (Italy) and Slovenia resulted in different effects of these polymorphisms on reproductive functions. Reproductively mature ewes (n = 100) from each breed were utilized to conduct the study. To evaluate the reproductive efficiency, lambing dates and number of lambs born were recorded per ewe; additionally, the duration in days from ram placement with ewes to lambing (DRPEL), litter size and the fertility rate were determined based on lambing dates. In each breed, there were eight nucleotide variations within the MTNR1A gene exon II, two of which (g.17355358 and g.17355171), respectively, resulted in a valine to isoleucine, and alanine to aspartic acid substitution, in amino acid sequence. The SNPs at position g.17355452 and g.17355458 were determined to have effects on reproductive performance. Genotypes C/C and C/T at g.17355452 in Bovska and Sarda and genotype A/A at g.17355458 in Istrian Pramenka were associated with a greater fertility and a lesser duration in days from ram placement with ewes to lambing. These findings confirmed that the nucleotide sequences of the MTNR1A gene could affect reproductive functions of Mediterranean sheep. • The reduction of the reproductive seasonality is a crucial goal in sheep-farming. • Knowing the genetic features of different dairy breed sheep could allow to improve the reproductive performances. • Polymorphisms in MTNR1A gene affect the seasonal reproductive activity in dairy sheep breeds. [ABSTRACT FROM AUTHOR]

Abstract: The ovine Melatonin Receptor 1A (MTNR1A) gene was structurally characterised and association between its variants and the reproductive seasonality was examined in a daughter design comprising three families of Rasa Aragonesa sheep breed. Sequencing of six Rasa Aragonesa ewes with extreme values for seasonality trait revealed 28 polymorphisms: 11 SNPs in the coding region (all in Exon 2), and 17 SNPs in the promoter region MTNR1A. All the substitutions in the coding region were found most likely lacking any phenotypic effect, because they are conservative mutations or were not part of the transmembrane domain. The silent mutations, which had shown association with reproductive seasonality in other breeds, were also found and genotyped in Rasa Aragonesa. The T allele of SNP606/RsaI of MNTR1A gene was associated with a greater percentage of oestrous cyclic ewes in the Rasa Aragonesa breed, indicating that this SNP may be in linkage disequilibrium with a mutation responsible for this trait close to MTNR1A, or in regulatory sequences of the gene. In this sense, several SNPs affecting a binding element for some transcription factors have been identified in the promoter region. The SNPs at 422 and 527 positions could constitute a binding element for some transcription factors (TFs), located in an EF2 and SRY consensus sites in the promoter region, respectively. Haplotype h 5 showed significant differences with the h 2 haplotype (66% compared to 49.2%) on oestrous cyclicity, thus these results are consistent with genotypic associations for each SNP. Haplotype with T, A and T alleles for SNPs 422, 677 (promoter region) and 612 (Exon 2) showed an increase of the percentage of oestrous cyclic ewes. Although some of these mutations have been associated with seasonal reproduction, further studies with a more appropriate animal design as well as functional studies of TF binding activity are needed. [Copyright &y& Elsevier]

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]

The variant red phenotype in Holstein cattle is indistinguishable from the traditional e/e recessive red phenotype caused by a mutation in melanocortin 1 receptor, but is inherited as a dominant trait in relation to black. Co-segregation analysis in four half-sib families segregating for variant red was conducted, excluding melanocortin 1 receptor, agouti signalling protein, attractin and melatonin receptor 1A as causative genes. However, variant red co-segregated with markers in a region of BTA27 that includes beta-defensin 103 ( DEFB103). Two newly identified microsatellites and 5 SNPs 5′ of DEFB103 were used for linkage mapping in four segregating families (LOD = 3.26). One haplotype was inherited in VR cattle in a 6-generation pedigree. [ABSTRACT FROM AUTHOR]

The article discusses the results of a study which examines whether the melatonin receptor 1A (MNTR1A) gene promoter polymorphism is associated with the predisposition and/of disease severity of adolescent idiopathic scoliosis (AIS). It was found that genotype and allele frequencies were comparable between case and control for SNP rs2119882 and that MTNR1A is not associated with the occurrence or curve severity of AIS.

A recent study suggested that the cadherin gene FAT exerts an influence on susceptibility to bipolar affective disorder (BPAD). We aimed to replicate this finding in a German sample (425 BPAD I and 419 controls). In addition, we performed a comprehensive linkage disequilibrium mapping of the whole genomic region of FAT and the neighboring circadian gene MTNR1A (48 single nucleotide polymorphisms (SNPs) covering 191 kb). No significant association was observed for SNPs located in the MTNR1A gene. In FAT, however, nine SNPs showed association, eight of them being located in the same haplotype block found to be associated with BPAD by Blair et al. The smallest P-value of 0.00028 (OR 1.71) was seen for non-synonymous SNP rs2637777. A combination of five markers including this marker showed a haplotype distribution with a nominal P-value of 1.8 × 10−5 that withstands correction for multiple testing. While the control allele frequencies between our sample and the samples of the original study are comparable, tendencies of risk allele frequencies are opposite. Possible explanations for this include potential differences in linkage disequilibrium structure between the German, Australian, UK, and Bulgarian populations sampling variation, multilocus effects and/or the occurrence of independent mutational events. We conclude that our results support an involvement of variation at the FAT gene in the etiology of BPAD, but that further work is needed both to clarify possible reasons for the observed risk allele differences and to ultimately identify the functionally relevant variant(s).Molecular Psychiatry (2008) 13, 277–284; doi:10.1038/sj.mp.4002111; published online 16 October 2007 [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the involvement of prolactin (PRL) on development of secondary skin follicles in cashmere goats. Goats were randomly assigned to either a bromocriptine treatment or control group. Samples of cashmere fiber, blood, and skin were collected from all goats after 1 mo. The results indicated that the length, growth rate, and diameter of fibers were not influenced (P > 0.05) by the inhibition of PRL resulting from the treatment with bromocriptine. There was a tendency for increases in total follicle number, primary and secondary follicle numbers, and in the ratio of secondary to primary follicles following treatment with bromocriptine, but these differences were not significant (P > 0.05). The percentage of active secondary follicles in anagen was increased (P < 0.05) in the bromocriptine-treated goats, but there was no effect of treatment on the percentage of active primary follicles. Bromocriptine decreased (P < 0.05) circulating concentrations of PRL and Insulin-like growth factor 1 (IGF1) and increased (P < 0.05) those of melatonin (MT), but there was no effect of this treatment on the serum concentrations of cortisol, growth hormone, tetraiodothyronine, and triiodothyronine. In bromocriptine-treated goats, mRNA expressions of PRL and MT membrane receptor 1a (MTNR1a) were decreased (P < 0.05) and mRNA expression of MT nuclear receptor (RORα) was increased (P < 0.05), but there was no effect of the treatment on expression of long PRL receptor, short PRL receptor, MT membrane receptor 1b and IGF1. It is concluded that inhibition of PRL promotes secondary hair follicle development in the anagen phase, possibly by downregulating MTNR1a and up-regulating RORα gene expression in the skin., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

High ambient temperature exhibits a retrograde effect on buffalo reproduction because of heat stress. Moreover, melatonin is known to regulate reproductive changes in seasonally reproductive animals by binding to high affinity, G protein–coupled receptors. The M TNR1A gene is a prime receptor, mediating the effect of melatonin at the neuroendocrine level to control seasonal reproduction. In sheep, the role of melatonin is well known; however, studies have not been conducted in buffalo to determine its effect during favorable and unfavorable breeding seasons. Therefore, the present study aimed to (1) determine the expression of MTNR1A , ERα, ERβ , and PR gene transcripts in the ovarian follicles of buffalo during the summer and winter seasons and (2) analyze melatonin, 17β-estradiol, and progesterone concentrations in the follicular fluid of buffalo during both seasons. Murrah buffalo ovaries were collected during both the summer (May–June) and winter (December–January) seasons. All visible ovarian follicles were allocated into one of three groups: (1) small (8–9.9 mm); (2) medium (10–11.9 mm); and (3) large (12–14 mm). Follicular fluid was aspirated from each group of follicles for hormone analyses. The granulosa cells were processed for RNA extraction. Furthermore, they were subjected to real-time quantitative PCR to analyze the expression (relative quantification) of MTNR1A, ERα, ERβ, and PR in each follicular group. The expression of MTNR1A gene transcript decreased with the increasing size of the follicle and intrafollicular melatonin concentration. Expression of ERα and PR remained unaffected by the season and was similar (P > 0.05) in all groups. Expression of ERβ was higher (P < 0.05) in summer than winter; nevertheless, small-sized follicles from the summer exhibited higher (P < 0.05) expressions than medium- and large-sized follicles. The overall intrafollicular melatonin concentration was positively correlated (P < 0.05) with 17β-estradiol and progesterone concentrations. In conclusion, the decreased expression of MTNR1A and increased concentration of intrafollicular melatonin with the increasing size of the follicle indicates a probable role in folliculogenesis and ovulation in buffalo. [ABSTRACT FROM AUTHOR]

Objective: In birds, three types of melatonin receptors (MTNR1A, MTNR1B, and MTNR1C) have been cloned. Previous researches have showed that three melatonin receptors played an essential role in reproduction and ovarian physiology. However, the association of polymorphisms of the three receptors with duck reproduction traits and egg quality traits is still unknown. In this test, we chose MTNR1A, MTNR1B, and MTNR1C as candidate genes to detect novel sequence polymorphism and analyze their association with egg production traits in Shaoxing duck, and detected their mRNA expression level in ovaries., Methods: In this study, a total of 785 duck blood samples were collected to investigate the association of melatonin receptor genes with egg production traits and egg quality traits using a direct sequencing method. And 6 ducks representing two groups (3 of each) according to the age at first eggs (at 128 days of age or after 150 days of age) were carefully selected for quantitative real-time polymerase chain reaction., Results: Seven novel polymorphisms (MTNR1A: g. 268C>T, MTNR1B: g. 41C>T, and g. 161T>C, MTNR1C: g. 10C>T, g. 24A>G, g. 108C>T, g. 363 T>C) were detected. The single nucleotide polymorphism (SNP) of MTNR1A (g. 268C>T) was significantly linked with the age at first egg (p<0.05). And a statistically significant association (p<0.05) was found between MTNR1C g.108 C>T and egg production traits: total egg numbers at 34 weeks old of age and age at first egg. In addition, the mRNA expression level of MTNR1A in ovary was significantly higher in late-mature group than in early-mature group, while MTNR1C showed a contrary tendency (p<0.05)., Conclusion: These results suggest that identified SNPs in MTNR1A and MTNR1C may influence the age at first egg and could be considered as the candidate molecular marker for identify early maturely traits in duck selection and improvement.