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Loss-of-Function Mutation in Tryptophan Hydroxylase-2 Identified in Unipolar Major Depression

Department of Cell Biology, Center for Models of Human Disease, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC 27710, USA.
Neuron (Impact Factor: 15.98). 02/2005; 45(1):11-6. DOI: 10.1016/j.neuron.2004.12.014
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ABSTRACT Dysregulation of central serotonin neurotransmission has been widely suspected as an important contributor to major depression. Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, three subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression.

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    • "It has been implicated in major depression, suicidal behaviour, bipolar disorder, obsessivecompulsive disorder and other psychiatric disorders [32]. The most frequently studied functional single nucleotide polymorphism (SNP) is TPH2 1463G>A (p.R441H), which results in approximately 80% loss of function in 5-HT production [33], however this SNP was not found in Slovenian population [39]. "
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    ABSTRACT: Heritability plays an important role in the development and expression of alcohol dependence. The present genetic association study explored the role of TPH2 polymorphisms and their haplotypes to investigate its role in alcohol dependence and comorbid psychopathological symptoms. The sample included 101 subjects currently diagnosed as alcohol abusers, 100 abstinent alcohol-dependent subjects and 97 healthy controls. Subjects were genotyped for TPH2 rs4570625, rs1843809, rs7305115, rs4290270. TPH2 genotypes were not associated with alcohol dependence, but GGAA haplotype was less common (p = 0.038) and GTAA and GGGT were more common (p = 0.011 and p = 0.021 respectively) in currently dependent patients compared to controls. Exploratory analysis of genotypes in currently dependent patients showed that rs1843809 was associated with depressive and aggressive traits (p = 0.045 and p = 0.001, respectively), rs4290270 with depressive and anxiety traits (p = 0.040 and p = 0.025, respectively) and rs4570625 with aggressive traits (p = 0.011). In abstinent subjects rs1843809 genotype was associated with traits of social anxiety (p = 0.003). Only association between rs1843809 and the BDHI score (p = 0.001) and associations between GTAA haplotype and Zung Anxiety Scale and BDHI score (p = 0.001 and p < 0.001, respectively) in currently dependent patients remained significant after applying the Bonferroni's correction. Our findings support a potential role of TPH2 in alcohol dependence. TPH2 genetic variability may be also associated with anxiety and aggression traits in alcohol dependent subjects. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Neuroscience Letters 07/2015; DOI:10.1016/j.neulet.2015.07.037 · 2.06 Impact Factor
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    • "Genetic or epigenetic factors affecting TPH2 gene expression or catalytic properties may alter 5-HT neurotransmission and thereby modify behavioral traits, drug responses, and disease susceptibility. In fact, a loss-of-function mutation in human TPH2 gene was identified in patients with major depression (Zhang et al. 2005), and a loss-offunction mutation in mice was associated with a reduced aggressive behavior (Kulikov et al. 2005). Also, psychiatric disorders such as bipolar disorder (Lopez et al. 2007), attention deficit/hyperactivity disorder (Walitza et al. 2005), and suicidality (Zill et al. 2004), have been associated with TPH2 promoter polymorphisms. "
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    ABSTRACT: Serotonin (5-HT) is a neurotransmitter involved in many aspects of the neuronal function. The synthesis of 5-HT is initiated by the hydroxylation of tryptophan, catalyzed by tryptophan hydroxylase (TPH). Two isoforms of TPH (TPH1 and TPH2) have been identified, with TPH2 almost exclusively expressed in the brain. Following TPH2 discovery, it was reported that polymorphisms of both gene and non-coding regions are associated with a spectrum of psychiatric disorders. Thus, insights into the mechanisms that specifically regulate TPH2 expression and its modulation by exogenous stimuli may represent a new therapeutic approach to modify serotonergic neurotransmission. To this aim, a CNS-originated cell line expressing TPH2 endogenously represents a valid model system. In this study, we report that TPH2 transcript and protein are modulated by neuronal differentiation in the cell line A1 mes-c-myc (A1). Moreover, we show luciferase activity driven by the human TPH2 promoter region and demonstrate that upon mutation of the NRSF/REST responsive element, the promoter activity strongly increases with cell differentiation. Our data suggest that A1 cells could represent a model system, allowing an insight into the mechanisms of regulation of TPH2 and to identify novel therapeutic targets in the development of drugs for the management of psychiatric disorders.
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    • "It has been demonstrated that depression is associated with poor prognosis in patients with HF, with higher prevalence rates of depression being associated with higher NYHA functional class [7] [8] [9] [10]. Many psychiatric disorders, including anxiety and depression , are thought to be related to dysfunction in serotonin (5-HT) neurotransmission in the brain [11], and a single nucleotide polymorphism (SNP) G1463A in the rate-limiting enzyme of brain 5-HT synthesis tryptophan hydroxylase-2 (TPH2), which results in ~ 80% decrease in the enzymatic activity, is detected in depression patients at a significantly higher frequency than in control subjects [12]. Interestingly, a recent study has revealed that inbred mouse strains have a similar loss-of-function SNP C1473G in mouse TPH2 gene, with C57Bl/6 and BALB/c strains being homozygous for wild-type (1473C) and loss-of-function (1473G) alleles, respectively [13]. "
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