A functional alternative splicing mutation in human tryptophan hydroxylase-2

Zhang, X.; Nicholls, Peter J.; Laje, Gonzalo; Sotnikova, Tatyana D.; Gainetdinov, Raul R.; Albert, Paul R.; Rajkowska, Grażyna; Stockmeier, C.A.; Speer, Marcy C.; Steffens, David C.; Austin, Mark C.; McMahon, Francis J.; Krishnan, K. Ranga Rama; García-Blanco, Mariano A.; Caron, Marc G.

doi:10.1097/01.yic.0000405901.80483.0b

Cited by 4 publications

(6 citation statements)

References 38 publications

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“…29 These observations as well as the recent characterization of a dominant negative form of TPH2 significantly affecting 5-HT synthesis that is present in roughly 20% of the general population may justify consideration of such a genotyping strategy. 32,33 The present study shows that both synthesis and SERTmediated reuptake are essential for maintaining proper intraneuronal 5-HT levels and persistent blockade of SERT by SSRIs exacerbates 5-HT deficiency in subjects with impaired TPH2 function. Finally, supplemental treatments with 5-HTP could prevent depletions caused by SSRIs in subjects with 5-HT synthesis deficiency.…”

Section: ■ Results and Discussionmentioning

confidence: 60%

Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice

Siesser

Sachs

Ramsey

et al. 2012

ACS Chem. Neurosci.

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Selective serotonin reuptake inhibitors (SSRIs) are a major class of antidepressants that act by blocking inward transport of serotonin (5-HT) into presynaptic neurons mediated by the serotonin transporter (SERT). Both reuptake and ongoing synthesis are essential in supporting intraneuronal serotonin concentrations in serotonergic neurons. A rare mutation in tryptophan hydroxylase 2 (Tph2), the rate limiting enzyme for 5-HT synthesis, was identified in several patients with major depression, and knock-in mice expressing the analogous mutation (R439H Tph2 KI) show 80% reduction in 5-HT synthesis and tissue levels. Chronic treatment with SSRIs (fluoxetine and paroxetine) resulted in a dramatic further depletion of 5-HT tissue levels in R439H Tph2 KI mice (down to 1-3% of wild type levels) while having little effects in wild-type controls. Treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) restored 5-HT tissue content in mutant mice, and cotreatment with 5-HTP and fluoxetine essentially prevented the depleting effect of a chronic SSRI. These data demonstrate that chronic SSRI treatment could further exacerbate the 5-HT deficiency in Tph2 mutation carriers, and this can be prevented by 5-HTP supplementation.

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Section: ■ Results and Discussionmentioning

confidence: 60%

Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice

Siesser

Sachs

Ramsey

et al. 2012

ACS Chem. Neurosci.

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show abstract

“…It is noteworthy that a C-terminal truncated TPH2 splice variant (TPH2-TR), which lacks TPH2 enzyme activity, dominant-negatively affects the full-length TPH2 function and results in reduced 5-HT synthesis [88]. Accordingly, another strategy for the modulation of TPH2 activity is to modify the alternative splicing of TPH 2 pre-mRNA.…”

Section: Tph2 As An Emerging Therapeutic Target For Stress Disordersmentioning

confidence: 99%

Tryptophan hydroxylase-2: An emerging therapeutic target for stress disorders

Chen

Miller

2013

Biochemical Pharmacology

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Serotonin (5-HT) has been long recognized to modulate the stress response, and dysfunction of 5-HT has been implicated in numerous stress disorders. Accordingly, the 5-HT system has been targeted for the treatment of stress disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT synthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. With a decade of extensive investigation, it is now recognized that: 1) TPH2 exhibits a highly flexible gene expression that is modulated by an increasing number of internal and external environmental factors including the biological clock, stressors, endogenous hormones, and antidepressant therapies; and 2) genetically determined TPH2 activity is linked to a growing body of stress-related neuronal correlates and behavioral traits. These findings reveal an active role of TPH2 in the stress response and provide new insights into the long recognized but not yet fully understood 5-HT-stress interaction. As a major modulator of 5-HT neurotransmission and the stress response, TPH2 is of both pathophysiological and pharmacological significance, and is emerging as a new therapeutic target for the treatment of stress disorders. Given that numerous antidepressant therapies influence TPH2 gene expression, TPH2 is already inadvertently targeted for the treatment of stress disorders. With increased understanding of the regulation of TPH2 activity we can now purposely utilize TPH2 as a target to develop new or optimize current therapies, which are expected to greatly improve the prevention and treatment of a wide variety of stress disorders.

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“…More recently, Zhang et al [2010a] reported that a common SNP (G>A, rs1386493) in intron 5 of h TPH 2 decreases efficiency of normal RNA splicing and results in a truncated TPH2 protein (TPH2‐TR) by alternative splicing. This TPH2‐TR lacks TPH2 enzyme activity but dominant‐negatively affects full‐length TPH2 function, causing reduced 5‐HT production [Zhang et al, 2010a].…”

Section: Introductionmentioning

confidence: 99%

“…This TPH2 mRNA variant is 2,992‐bp long and comprises six or seven exons, with the first five exons identical with the normal TPH2 mRNA while the last two exons are derived from intron 5. Hence, this shortened mRNA variant results not only from transcriptional regulation through alternative promoter usage, but also from post‐transcriptional regulation by alternative splicing, which is affected by an exon–intron boundary SNP (rs1386493) as mentioned above [Zhang et al, 2010a]. As for the strong antisense promoter in TPH 2 5′‐UTR, it may transcribe an antisense non‐coding RNA that partially overlaps the conventional TPH 2 mRNA, such that dsRNA might be formed to regulate TPH 2 gene expression.…”

Section: Introductionmentioning

confidence: 99%

Advances in tryptophan hydroxylase‐2 gene expression regulation: New insights into serotonin–stress interaction and clinical implications

Chen

Miller

2012

American J of Med Genetics Pt B

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Serotonin (5-HT) modulates the stress response by interacting with the hormonal hypothalamic-pituitary-adrenal (HPA) axis and neuronal sympathetic nervous system (SNS). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. While TPH2 genetic variance has been linked to numerous behavioral traits and disorders, findings on TPH2 gene expression have not only reinforced, but also provided new insights into, the long-recognized but not yet fully understood 5-HT-stress interaction. In this review, we summarize advances in TPH2 expression regulation and its relevance to the stress response and clinical implications. Particularly, based on findings on rhesus monkey TPH2 genetics and other relevant literature, we propose that: 1) upon activation of adrenal cortisol secretion, the cortisol surge induces TPH2 expression and de novo 5-HT synthesis; 2) the induced 5-HT in turn inhibits cortisol secretion by modulating the adrenal sensitivity to ACTH via the suprachiasmatic nuclei (SCN)-SNS-adrenal system, such that it contributes to the feedback inhibition of cortisol production; 3) basal TPH2 expression or 5-HT synthesis, as well as early-life experience, influence basal cortisol primarily via the hormonal HPA axis; and 4) 5′- and 3′-regulatory polymorphisms of TPH2 may differentially influence the stress response, presumably due to their differential roles in gene expression regulation. Our increasing knowledge of TPH2 expression regulation not only helps us better understand the 5-HT-stress interaction and the pathophysiology of neuropsychiatric disorders, but also provides new strategies for the treatment of stress-associated diseases.

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A functional alternative splicing mutation in human tryptophan hydroxylase-2

Cited by 4 publications

References 38 publications

Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice

Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice

Tryptophan hydroxylase-2: An emerging therapeutic target for stress disorders

Advances in tryptophan hydroxylase‐2 gene expression regulation: New insights into serotonin–stress interaction and clinical implications

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