Context:The tryptophan hydroxylase 2 (TPH2) gene encodes the first (also the rate-limiting) enzyme in the serotonin biosynthetic pathway. Despite reports of possible associations between polymorphisms in human TPH2 and many psychiatric disorders, including bipolar disorder (BPD), the functional effect and susceptibility loci of such polymorphisms for BPD have not yet been identified. Objectives:To examine the association of TPH2 with BPD and to identify the functional variants that may be involved in the pathophysiological development of BPD.Design, Setting, and Patients: We systematically screened all exons and promoters of the TPH2 gene in Han Chinese subjects to identify sequence variants. Association tests were conducted in 105 cases and 106 control subjects using single-locus, linkage disequilibrium, and haplotype analyses. Two promoter and one exon 2 single-nucleotide polymorphisms were examined for their functional role using a reporter gene system and enzyme activity assay, respectively. Additional statistical analysis was performed to study the interaction between the 2 TPH genes in 205 study participants with TPH1 and TPH2 genotype data.Results: Significant haplotype association of TPH2 polymorphisms and BPD was identified (P Ͻ.001). In addition, allelic alteration of polymorphisms in the promoter region and exon 2 of TPH2 caused noteworthy functional losses in promoter and enzyme activities, respectively, indicating the potential susceptibility loci for BPD. We found that the odds ratio changed from 3.73 of the TAG haplotype to 4.81 or 1.68, depending on the combined effect of both TPH genotypes. These data suggested an interaction between the 2 TPH genes to confer a risk for BPD.Conclusions: This study supports the involvement of TPH2 in the etiology of BPD, and the functional singlenucleotide polymorphisms identified herein might be the susceptibility loci for BPD. Although the interaction between the 2 TPH genes merits further investigation, our findings suggest that the interactive effect should be considered in future studies of serotonin-related disorders.
Background: Disturbances in serotonin neurotransmission are implicated in the etiology of many psychiatric disorders, including bipolar affective disorder (BPD). The tryptophan hydroxylase gene (TPH), which codes for the enzyme catalyzing the rate-limiting step in serotonin biosynthetic pathway, is one of the leading candidate genes for psychiatric and behavioral disorders. In a preliminary study, we found that TPH1 intron7 A218C polymorphism was associated with BPD. This study was designed to investigate sequence variants of the TPH1 gene in Taiwanese and to test whether the TPH1 gene is a susceptibility factor for the BPD.
The rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase 2 (TPH2), is one of the most promising candidate genes for psychiatric disorders. Although evidence strongly suggests that the TPH2 is significant in the etiology of major depression and anxiety disorder, whether it also contributes to the etiology of peripartum major depression and anxiety disorder, a specific subtype influenced considerably by other environmental factors like hormones, is unclear. This study investigated the role of TPH2 in the etiology of peripartum major depression and anxiety disorder in a Han Chinese population in Taiwan. Six single nucleotide polymorphisms were selected from previously profiled genetic information of TPH2 in Han Chinese. A cohort of postpartum Chinese women that included 117 patients with major depression, anxiety disorder, or both and 83 healthy controls were genotyped with selected TPH2 markers. The TPH2 2755A allele was found only in women with peripartum major depression and anxiety disorder (p = 0.043) and exhibited a dominant gene action (p = 0.038) with an estimated disease risk of 1.73. Although the sample size is small, results from this study suggest that the TPH2 C2755A polymorphism may represent a population-specific risk factor for peripartum major depression and anxiety disorder, perhaps by interacting with hormones.
POU-homeodomain transcription factor POU3F2 is a critical transcription factor that participates in neuronal differentiation. However, little is known about its downstream mediators. Here genome-wide analyses of a human neuronal differentiation cell model, NT2D1, suggested neurotrophin-3 (NTF3), a key mediator of neuronal development during the early neurogenic period, as a putative regulatory target of POU3F2. Western blot, cDNA microarray, and real-time quantitative PCR analyses showed that POU3F2 and NTF3 were upregulated during neuronal differentiation. Next-generation-sequence-based POU3F2 chromatin immunoprecipitation-sequencing and genome-wide in silico prediction demonstrated that POU3F2 binds to the NTF3 promoter during neuronal differentiation. Furthermore, unidirectional deletion or mutation of the binding site of POU3F2 in the NTF3 promoter decreased promoter-driven luciferase activity, indicating that POU3F2 is a positive regulator of NTF3 promoter activity. While NTF3 knockdown resulted in decreased viability and differentiation of NT2D1 cells, and POU3F2 knockdown downregulated NTF3 expression, recombinant NTF3 significantly rescued viable neuronal cells from NTF3- or POU3F2-knockdown cell cultures. Moreover, immunostaining showed colocalization of POU3F2 and NTF3 in developing mouse neurons. Thus, our data suggest that NTF3 is a novel target gene of POU3F2 and that the POU3F2/NTF3 pathway plays a role in the process of neuronal differentiation.Electronic supplementary materialThe online version of this article (10.1007/s12035-018-0995-y) contains supplementary material, which is available to authorized users.
Plant seeds naturally accumulate storage reserves (proteins, carbohydrates, lipids) that are mobilized during germination to provide energy and raw materials to support early seedling growth. Seeds have been exploited as bioreactors for the production to foreign materials, but stable, high level expression has been elusive, in part due to the intrinsic bias for producing the natural reserves in their typical proportions. To identify mutants governing seed filling, we screened a population of mutagenized Arabidopsis plants for a mutant that failed to fill its seeds. Here we report the identification of ssp1, a recessive, viable mutant that accumulates approximately 15% less protein than wildtype seeds. Molecular analyses revealed that ssp1 is due to the introduction of a premature stop codon in CRU3, one of the major cruciferin genes. Unlike many other reserve mutants or transgenic lines in which seed storage protein levels are reduced by antisense/RNAi technologies, ssp1 exhibits low level compensation by other reserves, and represents a mutant background that might prove useful for high level expression of foreign proteins. To test this hypothesis, we used a bean phytohemagglutinin (PHA) gene as a reporter and compared PHA expression levels in single copy insertion lines in ssp1 vs. wildtype. These near isogenic lines allow reporter protein levels to be compared without the confounding and sometimes unknown influences of transgene copy number and position effects on gene expression. The ssp1 lines consistently accumulated more PHA than the backcrossed counterparts, with increases ranging from 12% to 126%. This proof of principle study suggests that similar strategies in crop plants may improve the yield of foreign proteins of agronomic and economic interest.
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