{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTryptophan hydroxylase‐2 (TPH2) is the brain‐exclusive, rate‐limiting enzyme for serotonin biosynthesis. Multiple studies have detailed its biochemical and regulatory features – for example, a loss‐of‐function mutation (G1463A) that slashes serotonin production by around 80% illustrates its pivotal catalytic role."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Brain‐selective expression of TPH2, undetectable in peripheral tissues, further emphasizes its central role in neuromodulation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", with postmortem examinations confirming its unique distribution and absence of compensatory expression of the non‐neuronal isoform."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In depressed suicide cases, elevated TPH2 expression in the dorsal raphe suggests a compensatory upregulation in response to serotonin deficiency"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while regulatory studies indicate that vitamin D–mediated mechanisms via vitamin D–responsive elements can significantly induce TPH2 expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In vitro investigations also show that the TPH2 promoter and 5′-UTR, including evidence of allelic mRNA imbalances and RNA editing, play critical roles in dictating gene expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": " Moreover, analyses of alternative splicing and RNA editing have revealed additional layers of TPH2 regulation that modulate enzyme activity in the human brain"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", and even observations from serotonergic anomalies in conditions such as sudden infant death syndrome provide further context"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ").\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies of TPH2 have linked common polymorphisms to an array of psychiatric phenotypes. Candidate gene meta‐analyses and family–based association studies in attention–deficit/hyperactivity disorder (ADHD) have flagged TPH2 variants as showing significant, though heterogeneous, associations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "20"}]}, {"type": "t", "text": " Beyond ADHD, TPH2 variants have been repeatedly implicated in mood disorders: associations with major depression and bipolar disorder – including functionally detrimental substitutions like Pro206Ser that compromise enzyme stability – underline its contribution to affective dysregulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "31"}]}, {"type": "t", "text": " These findings support a model in which TPH2 gene variation can predispose individuals to affective disturbances, suicidal behavior, and even aspects of impulse control.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA complementary body of research has focused on how TPH2 variability influences neural circuits and clinical responses. Functional magnetic resonance imaging and electrophysiological paradigms have shown that regulatory variants in TPH2 – such as the G(–703)T polymorphism – modulate amygdala reactivity to emotional stimuli, with measurable impacts on both negative and positive affect."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "35"}]}, {"type": "t", "text": " Reviews and studies on treatment response further suggest that TPH2 polymorphisms may influence antidepressant outcomes and even placebo responsiveness"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": ", while electrophysiological recordings have identified additive effects of TPH2 and other serotonergic genes on early neural processing of emotional information."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "39"}]}, {"type": "t", "text": " Additionally, TPH2 variants have been linked to altered decision-making and cognitive control in tasks assessing executive function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "40", "end_ref": "45"}]}, {"type": "t", "text": " Finally, studies in specific populations – such as Korean women with social anxiety – underscore how TPH2 variation can affect amygdala responsiveness, with broader implications for understanding the neural basis of anxiety disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "46"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xiaodong Zhang, Raul R Gainetdinov, Jean-Martin Beaulieu, et al. 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