{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTyrosine hydroxylase (TH) is the rate‐limiting enzyme in catecholamine synthesis, whose activity is tightly regulated by multiple post‐translational mechanisms. Phosphorylation at key serine residues (e.g. Ser19, Ser31, and Ser40) modulates TH activity both directly and via changes in binding affinity for regulatory proteins such as 14–3–3 and coactivators including DJ–1. Structural studies have revealed that binding of L–DOPA to TH induces a conformational change by locking an N–terminal helix into the active site, thereby inhibiting the enzyme, whereas phosphorylation (notably at Ser40) counteracts this inhibition and stabilizes the enzyme. In addition, biochemical studies indicate that aberrant phosphorylation can flag TH for ubiquitin–proteasome–dependent degradation. These molecular insights underscore the complex, hierarchical regulation of TH that is essential for controlled dopamine biosynthesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in TH function are intimately linked to diverse neurological and systemic disorders. Mutations or deficiencies in TH cause dopa–responsive dystonia and are implicated in hereditary and sporadic forms of Parkinson disease, reflecting reduced dopamine synthesis in key brain regions. In addition, changes in TH expression or activity—whether due to genetic polymorphisms, epigenetic modifications, or dysregulation by microRNAs—have been associated with conditions including schizophrenia, essential hypertension, and even alterations in autonomic tone. Experimental models demonstrate that impaired TH activity can manifest in complex motor disorders and altered receptor sensitivities, while peripheral measurements of TH mRNA have been proposed as biomarkers in psychiatric conditions. Moreover, TH has emerged as a potential autoantigen in disorders such as vitiligo, further underscoring its broad clinical relevance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "20"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its enzymatic role, TH gene regulation is governed by a combination of promoter elements, epigenetic modifications, and interactions with transcriptional regulators that collectively determine cell type–specific expression. Studies in diverse tissues—from the retina and melanocytes to neural stem cells—demonstrate that methylation status and polymorphic variants within the TH locus (including VNTRs and single nucleotide polymorphisms) can influence gene transcription and, consequently, catecholamine production. Furthermore, integration of the TH gene into broader genomic regions (e.g. the IGF2–INS–TH locus) suggests that TH variability may contribute to phenotypes ranging from altered stress responses and personality traits to predisposition for nicotine dependence and metabolic conditions, highlighting its multifunctional role in both neural and peripheral systems."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "38"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ingo T Lehmann, Larisa Bobrovskaya, Sarah L Gordon, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M601935200"}], "href": "https://doi.org/10.1074/jbc.M601935200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16731528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16731528"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Veronika Obsilova, Eliska Nedbalkova, Jan Silhan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The 14-3-3 protein affects the conformation of the regulatory domain of human tyrosine hydroxylase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi7019468"}], "href": "https://doi.org/10.1021/bi7019468"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18181650"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18181650"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Shizuma Ishikawa, Takahiro Taira, Takeshi Niki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oxidative status of DJ-1-dependent activation of dopamine synthesis through interaction of tyrosine hydroxylase and 4-dihydroxy-L-phenylalanine (L-DOPA) decarboxylase with DJ-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.019950"}], "href": "https://doi.org/10.1074/jbc.M109.019950"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19703902"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19703902"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Shizuma Ishikawa, Takahiro Taira, Kazuko Takahashi-Niki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human DJ-1-specific transcriptional activation of tyrosine hydroxylase gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.137034"}], "href": "https://doi.org/10.1074/jbc.M110.137034"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20938049"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20938049"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Øyvind Halskau, Ming Ying, Anne Baumann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Three-way interaction between 14-3-3 proteins, the N-terminal region of tyrosine hydroxylase, and negatively charged membranes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.027706"}], "href": "https://doi.org/10.1074/jbc.M109.027706"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19801645"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19801645"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "María Teresa Bueno-Carrasco, Jorge Cuéllar, Marte I Flydal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-021-27657-y"}], "href": "https://doi.org/10.1038/s41467-021-27657-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35013193"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35013193"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Akira Nakashima, Keiji Mori, Yoko S Kaneko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphorylation of the N-terminal portion of tyrosine hydroxylase triggers proteasomal digestion of the enzyme."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2011.03.020"}], "href": "https://doi.org/10.1016/j.bbrc.2011.03.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21392500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21392500"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Georg F Hoffmann, Birgit Assmann, Christa Bräutigam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Neurol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ana.10632"}], "href": "https://doi.org/10.1002/ana.10632"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12891655"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12891655"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Fangwen Rao, Lian Zhang, Jennifer Wessel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis: discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.106.682302"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.106.682302"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17698732"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17698732"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Ina Giegling, Daniel Moreno-De-Luca, Dan Rujescu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dopa decarboxylase and tyrosine hydroxylase gene variants in suicidal behavior."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet B Neuropsychiatr Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.b.30599"}], "href": "https://doi.org/10.1002/ajmg.b.30599"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17948905"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17948905"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Thomas Gerald Beach, Charles H Adler, Lucia I Sue, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduced striatal tyrosine hydroxylase in incidental Lewy body disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Neuropathol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00401-007-0313-7"}], "href": "https://doi.org/10.1007/s00401-007-0313-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17985144"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17985144"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Min-Ju Kim, Kyungsook Ahn, Seong-Hoon Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SIRT1 regulates tyrosine hydroxylase expression and differentiation of neuroblastoma cells via FOXO3a."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2009.03.007"}], "href": "https://doi.org/10.1016/j.febslet.2009.03.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19285077"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19285077"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Fabienne Clot, David Grabli, Cécile Cazeneuve, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awp084"}], "href": "https://doi.org/10.1093/brain/awp084"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19491146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19491146"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Liang Liu, Fujun Jia, Guozhen Yuan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tyrosine hydroxylase, interleukin-1beta and tumor necrosis factor-alpha are overexpressed in peripheral blood mononuclear cells from schizophrenia patients as determined by semi-quantitative analysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Psychiatry Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.psychres.2008.10.024"}], "href": "https://doi.org/10.1016/j.psychres.2008.10.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20067853"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20067853"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Kuixing Zhang, Lian Zhang, Fangwen Rao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human tyrosine hydroxylase natural genetic variation: delineation of functional transcriptional control motifs disrupted in the proximal promoter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Cardiovasc Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCGENETICS.109.904813"}], "href": "https://doi.org/10.1161/CIRCGENETICS.109.904813"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20124442"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20124442"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Albert H Kim, Mark Reimers, Brion Maher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Schizophr Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.schres.2010.07.002"}], "href": "https://doi.org/10.1016/j.schres.2010.07.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20675101"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20675101"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Laura M Hack, Gursharan Kalsi, Fazil Aliev, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Limited associations of dopamine system genes with alcohol dependence and related traits in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Alcohol Clin Exp Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1530-0277.2010.01353.x"}], "href": "https://doi.org/10.1111/j.1530-0277.2010.01353.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21083670"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21083670"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "E Helen Kemp, Sherif Emhemad, Samia Akhtar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autoantibodies against tyrosine hydroxylase in patients with non-segmental (generalised) vitiligo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Dermatol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1600-0625.2010.01181.x"}], "href": "https://doi.org/10.1111/j.1600-0625.2010.01181.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21158937"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21158937"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Samuel J Rose, Xin Y Yu, Ann K Heinzer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A new knock-in mouse model of l-DOPA-responsive dystonia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awv212"}], "href": "https://doi.org/10.1093/brain/awv212"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26220941"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26220941"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "G Paolisso, M Barbieri, M R Rizzo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Low insulin resistance and preserved beta-cell function contribute to human longevity but are not associated with TH-INS genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Gerontol (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0531-5565(01)00148-6"}], "href": "https://doi.org/10.1016/s0531-5565(01"}, {"type": "t", "text": "00148-6) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11738155"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11738155"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Alfonso Lavado, Glen Jeffery, Victoria Tovar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ectopic expression of tyrosine hydroxylase in the pigmented epithelium rescues the retinal abnormalities and visual function common in albinos in the absence of melanin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2006.03657.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2006.03657.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16445854"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16445854"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Keizo Yoshida, Hisashi Higuchi, Hitoshi Takahashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Influence of the tyrosine hydroxylase val81met polymorphism and catechol-O-methyltransferase val158met polymorphism on the antidepressant effect of milnacipran."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Psychopharmacol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hup.907"}], "href": "https://doi.org/10.1002/hup.907"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18023073"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18023073"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Santiago Rodríguez, Tom R Gaunt, Sandra D O'Dell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddh070"}], "href": "https://doi.org/10.1093/hmg/ddh070"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14749349"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14749349"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Seong-Tae Kim, Yu Cheng, Fang-Chi Hsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prostate cancer risk-associated variants reported from genome-wide association studies: meta-analysis and their contribution to genetic Variation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prostate (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/pros.21208"}], "href": "https://doi.org/10.1002/pros.21208"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20564319"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20564319"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Lee K Marles, Eva M Peters, Desmond J Tobin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tyrosine hydroxylase isoenzyme I is present in human melanosomes: a possible novel function in pigmentation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Dermatol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1034/j.1600-0625.2003.120108.x"}], "href": "https://doi.org/10.1034/j.1600-0625.2003.120108.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12631248"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12631248"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Javier Bernácer, Lucía Prensa, José Manuel Giménez-Amaya "}, {"type": "b", "children": [{"type": "t", "text": "Distribution of GABAergic interneurons and dopaminergic cells in the functional territories of the human striatum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0030504"}], "href": "https://doi.org/10.1371/journal.pone.0030504"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22272358"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22272358"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Francesco Lescai, Helene Blanché, Almut Nebel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human longevity and 11p15.5: a study in 1321 centenarians."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2009.54"}], "href": "https://doi.org/10.1038/ejhg.2009.54"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19367319"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19367319"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Sirigiri Divijendra Natha Reddy, Suresh K Rayala, Kazufumi Ohshiro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Multiple coregulatory control of tyrosine hydroxylase gene transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1101193108"}], "href": "https://doi.org/10.1073/pnas.1101193108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21368136"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21368136"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Soo Min Kim, Jae Won Yang, Mi Jung Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of human tyrosine hydroxylase gene by neuron-restrictive silencer factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2006.05.142"}], "href": "https://doi.org/10.1016/j.bbrc.2006.05.142"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16764822"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16764822"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Mamoru Tochigi, Takeshi Otowa, Hiroyuki Hibino, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Combined analysis of association between personality traits and three functional polymorphisms in the tyrosine hydroxylase, monoamine oxidase A, and catechol-O-methyltransferase genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurosci Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neures.2005.11.003"}], "href": "https://doi.org/10.1016/j.neures.2005.11.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16360899"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16360899"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Lambert H J Lambooy, Corrie E M Gidding, Lambert P van den Heuvel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Real-time analysis of tyrosine hydroxylase gene expression: a sensitive and semiquantitative marker for minimal residual disease detection of neuroblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12576454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12576454"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Tae Eun Kim, Mi Jung Park, Eun Jung Choi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cloning and cell type-specific regulation of the human tyrosine hydroxylase gene promoter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2003.11.029"}], "href": "https://doi.org/10.1016/j.bbrc.2003.11.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14651989"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14651989"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Martin Göttle, Cecilia N Prudente, Rong Fu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Neurol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ana.24191"}], "href": "https://doi.org/10.1002/ana.24191"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24891139"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24891139"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Tamás Arányi, Baptiste A Faucheux, Olfa Khalfallah, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The tissue-specific methylation of the human tyrosine hydroxylase gene reveals new regulatory elements in the first exon."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2005.03173.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2005.03173.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15953356"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15953356"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Richard J L Anney, Craig A Olsson, Mehrnoush Lotfi-Miri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nicotine dependence in a prospective population-based study of adolescents: the protective role of a functional tyrosine hydroxylase polymorphism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacogenetics (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/00008571-200402000-00001"}], "href": "https://doi.org/10.1097/00008571-200402000-00001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15077008"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15077008"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Michael Klintschar, Barbara Reichenpfader, Klaus-Steffen Saternus "}, {"type": "b", "children": [{"type": "t", "text": "A functional polymorphism in the tyrosine hydroxylase gene indicates a role of noradrenalinergic signaling in sudden infant death syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pediatr (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jpeds.2008.02.032"}], "href": "https://doi.org/10.1016/j.jpeds.2008.02.032"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18534229"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18534229"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Shraddha Pai, Peipei Li, Bryan Killinger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-019-09786-7"}], "href": "https://doi.org/10.1038/s41467-019-09786-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31053723"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31053723"}]}]}]}