TH

Summary

TH (tyrosine hydroxylase, HGNC:11782) is a protein-coding gene on chromosome 11p15.5, encoding Tyrosine 3-monooxygenase (P07101). Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, noradrenaline, and adrenaline.

The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 7054 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tyrosine hydroxylase deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 1,249 total — 52 pathogenic, 117 likely-pathogenic (top 2% of genes corpus-wide)
• GTEx eGene: eQTL in 14 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 40
• Drug target: yes — 1 curated mechanism-of-action drug
• Approved drugs (ChEMBL mechanism of action): 1 — Metyrosine
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.27 (unconstrained)
• MANE Select transcript: NM_000360
• Interaction hub: 3,006 STRING partners (top 2% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11782
Approved symbol	TH
Name	tyrosine hydroxylase
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	DYT5b
Ensembl gene	ENSG00000180176
Ensembl biotype	protein_coding
OMIM	191290
Entrez	7054

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 8 protein_coding, 6 nonsense_mediated_decay, 3 retained_intron

MANE Select: ENST00000352909

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 6, TSL 2: 1, TSL 3: 1, TSL 5: 3

ENST00000352909, ENST00000324155, ENST00000333684, ENST00000381168, ENST00000381175, ENST00000381178, ENST00000412076, ENST00000416223, ENST00000461172, ENST00000469226, ENST00000479437, ENST00000853117, ENST00000941211, ENST00000941212, ENST00001014565, ENST00001123687, ENST00001123688

RefSeq mRNA: 6 — MANE Select: NM_000360 NM_000360, NM_001440535, NM_001440536, NM_001440537, NM_199292, NM_199293

CCDS: CCDS31338, CCDS7730, CCDS7731

Canonical transcript exons

ENST00000352909 — 13 exons

Exon	Start	End
ENSE00001285442	2169650	2169871
ENSE00001607448	2165232	2165365
ENSE00003527173	2166887	2167032
ENSE00003545349	2166002	2166058
ENSE00003550033	2165668	2165763
ENSE00003559971	2168491	2168665
ENSE00003565862	2167866	2167933
ENSE00003584238	2168091	2168179
ENSE00003585927	2167435	2167485
ENSE00003596261	2166480	2166549
ENSE00003662445	2166633	2166768
ENSE00003901440	2163929	2164392
ENSE00004803380	2171697	2171815

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 94.90.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.8528 / max 461.9579, expressed in 169 samples.

Highest expression (Bgee): substantia nigra pars reticulata, substantia nigra pars compacta, male germ line stem cell (sensu Vertebrata) in testis, substantia nigra, midbrain.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TH is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 14 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Not Sun Exposed Suprapubic	eqtl	7.4e-34	+0.59	11:2175680:G:A
Skin Sun Exposed Lower leg	eqtl	1.4e-28	+0.44	11:2177188:G:T
Thyroid	eqtl	2.6e-17	-0.46	11:2166625:G:C
Esophagus Mucosa	eqtl	2.3e-09	+0.25	11:2168753:C:T
Brain Hippocampus	eqtl	9.0e-07	+0.41	11:2172832:A:C
Pancreas	eqtl	1.0e-06	+0.42	11:2175882:A:G
Ovary	eqtl	9.6e-06	+0.47	11:2168753:C:T
Lung	eqtl	5.4e-04	+1.07	11:2188739:C:T
Esophagus Muscularis	eqtl	7.7e-04	+0.24	11:2183487:C:T
Bladder	eqtl	1.9e-03	+0.53	11:2168753:C:T
Artery Coronary	eqtl	3.1e-03	+0.38	11:2192416:G:GC
Esophagus Gastroesophageal Junction	eqtl	5.5e-03	-0.33	11:1312172:C:T
Brain Hypothalamus	eqtl	7.8e-03	+0.22	11:2177029:G:A
Testis	eqtl	4.3e-02	+0.20	11:3138271:T:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
118191	1.6340	142
118190	0.1876	29
206160	0.0311	14

Top tissues by expression

showing 100 of 285 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
substantia nigra pars reticulata	UBERON:0001966	94.90	gold quality
substantia nigra pars compacta	UBERON:0001965	93.18	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.74	gold quality
substantia nigra	UBERON:0002038	86.19	gold quality
midbrain	UBERON:0001891	83.30	gold quality
right adrenal gland	UBERON:0001233	76.77	gold quality
adrenal gland	UBERON:0002369	76.75	gold quality
hypothalamus	UBERON:0001898	76.68	gold quality
left adrenal gland	UBERON:0001234	76.31	gold quality
left adrenal gland cortex	UBERON:0035825	74.95	gold quality
adrenal cortex	UBERON:0001235	72.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.04	gold quality
caudate nucleus	UBERON:0001873	71.74	gold quality
right lobe of liver	UBERON:0001114	68.38	gold quality
nucleus accumbens	UBERON:0001882	68.11	gold quality
ventral tegmental area	UBERON:0002691	65.65	gold quality
superior vestibular nucleus	UBERON:0007227	62.16	gold quality
right adrenal gland cortex	UBERON:0035827	60.53	gold quality
pituitary gland	UBERON:0000007	59.44	gold quality
putamen	UBERON:0001874	59.14	gold quality
inferior olivary complex	UBERON:0002127	58.36	silver quality
endocervix	UBERON:0000458	57.95	gold quality
adenohypophysis	UBERON:0002196	57.94	gold quality
adrenal tissue	UBERON:0018303	57.70	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	57.41	gold quality
liver	UBERON:0002107	56.68	gold quality
prefrontal cortex	UBERON:0000451	56.45	gold quality
forebrain	UBERON:0001890	56.10	gold quality
decidua	UBERON:0002450	55.99	gold quality
gall bladder	UBERON:0002110	55.11	gold quality
left ovary	UBERON:0002119	54.87	gold quality
cingulate cortex	UBERON:0003027	54.54	gold quality
telencephalon	UBERON:0001893	54.40	gold quality
brain	UBERON:0000955	54.35	gold quality
anterior cingulate cortex	UBERON:0009835	54.19	gold quality
central nervous system	UBERON:0001017	53.98	gold quality
lower esophagus mucosa	UBERON:0035834	53.85	gold quality
Ammon’s horn	UBERON:0001954	53.04	gold quality
frontal cortex	UBERON:0001870	53.03	gold quality
neocortex	UBERON:0001950	52.64	gold quality
right ovary	UBERON:0002118	52.49	gold quality
esophagus mucosa	UBERON:0002469	52.33	gold quality
medulla oblongata	UBERON:0001896	52.21	silver quality
ovary	UBERON:0000992	52.07	gold quality
urinary bladder	UBERON:0001255	51.59	gold quality
amygdala	UBERON:0001876	51.55	gold quality
pancreatic ductal cell	CL:0002079	51.52	silver quality
vagina	UBERON:0000996	51.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	51.23	gold quality
cerebral cortex	UBERON:0000956	51.15	gold quality
uterine cervix	UBERON:0000002	50.98	gold quality
subthalamic nucleus	UBERON:0001906	50.81	silver quality
metanephros	UBERON:0000081	50.60	gold quality
right frontal lobe	UBERON:0002810	50.51	gold quality
esophagus	UBERON:0001043	50.47	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
thymus	UBERON:0002370	50.36	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	50.05	gold quality
quadriceps femoris	UBERON:0001377	49.96	gold quality
epithelial cell of pancreas	CL:0000083	49.73	gold quality
ectocervix	UBERON:0012249	49.47	gold quality
vastus lateralis	UBERON:0001379	49.45	gold quality
skin of abdomen	UBERON:0001416	49.45	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	49.31	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
lower esophagus	UBERON:0013473	49.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	49.00	gold quality
fundus of stomach	UBERON:0001160	48.98	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
amniotic fluid	UBERON:0000173	48.61	silver quality
oviduct epithelium	UBERON:0004804	48.61	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
left uterine tube	UBERON:0001303	48.42	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
mucosa of transverse colon	UBERON:0004991	48.14	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
female reproductive system	UBERON:0000474	47.79	gold quality
metanephric glomerulus	UBERON:0004736	47.74	gold quality
nasal cavity epithelium	UBERON:0005384	47.70	gold quality
apex of heart	UBERON:0002098	47.61	gold quality
renal glomerulus	UBERON:0000074	47.60	gold quality
deltoid	UBERON:0001476	47.56	gold quality
layer of synovial tissue	UBERON:0007616	47.54	gold quality
kidney epithelium	UBERON:0004819	47.32	gold quality
right coronary artery	UBERON:0001625	47.27	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	2758.94
E-GEOD-93593	yes	8.03
E-HCAD-10	yes	4.28
E-ANND-3	no	1.77

HPA expression

RNA tissue specificity: Group enriched

51 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Substantia nigra	tissue	999.2
Locus coeruleus	tissue	573.7
Adrenal gland	tissue	185.6	high
Midbrain	tissue	99.5
Pons	tissue	48.8
Periaqueductal gray	tissue	32.0
Hypothalamus	tissue	18.8
Olfactory bulb	tissue	16.7
Caudate putamen	tissue	9.8
Frontal cortex	tissue	5.3
Hippocampal formation	tissue	5.0
Entorhinal cortex	tissue	5.0
Cerebral cortex	tissue	4.9	not detected
Retrosplenial and cingulate cortex	tissue	4.9
Prefrontal cortex	tissue	4.1
Insular cortex	tissue	3.8
Nucleus accumbens	tissue	3.6
Somatosensory cortex	tissue	3.4
Temporal cortex	tissue	3.3
Medulla oblongata	tissue	3.2
Adipose tissue	tissue	3.1	not detected
Motor cortex	tissue	2.1
Hippocampus	tissue	1.7	not detected
Pituitary gland	tissue	1.6
Vagina	tissue	1.4	not detected
Superior colliculi	tissue	1.4
Septum	tissue	1.3
Occipital cortex	tissue	1.3
Thalamus	tissue	1.0
Ventral forebrain	tissue	0.8
Skin 1	tissue	0.7	not detected
Spinal cord	tissue	0.7
Amygdala	tissue	0.6
Small intestine	tissue	0.5	not detected
Corpus callosum	tissue	0.5
Retrosplenial cortex	tissue	0.5
Putamen	tissue	0.4
Gallbladder	tissue	0.4	not detected
Testis	tissue	0.2	not detected
Pancreas	tissue	0.2	not detected
Basal ganglia	tissue	0.2	not detected
Choroid plexus	tissue	0.2
Cervix	tissue	0.1	not detected
Retina	tissue	0.1
Ovary	tissue	0.1	not detected
Urinary bladder	tissue	0.1	not detected
Placenta	tissue	0.1	not detected
Spleen	tissue	0.1	not detected
Prostate	tissue	0.1	not detected
Fallopian tube	tissue	0.1	not detected
Appendix	tissue	0.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 166; highest nTPM — Ventral tegmental area (311.2), Lateral hypothalamic area (96.2), Pedunculopontine tegmental nucleus (93.2), Median raphe nucleus (85.0), Supraoptic nucleus (63.4).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, AR, ARNT, ASCL1, ATF1, ATF2, ATF4, ATF5, BCL6, BMAL1, CEBPG, CLOCK, CREB1, CREM, CTF1, EGR1, ELK1, ENO1, EOMES, ESR1, ESR2, ETV1, FOS, FOSB, FOSL2, FOXA1, FOXA2, FOXN1, GATA3, GSC2, HAND1, HAND2, HIF1A, HMX1, HOXA4, HOXA5, JUN, JUNB, JUND

miRNA regulators (miRDB)

Targeting TH by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

9 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-3665	97.73	65.08	975
HSA-MIR-4786-5P	97.45	67.89	924
HSA-MIR-433-5P	94.67	64.82	99

Functional genomics

gnomAD constraint: pLI 3.33e-17, LOEUF 1.27, missense Z -1.03 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000352909 — one region, missense o/e 1.03.

Literature-anchored findings (GeneRIF, showing 40)

• Gene expression found upregulated by Glial cell line-derived neurotrophic factor in human neuroblastoma cell lines (PMID:12358785)
• A review of investigations on the possible contribution and potential role of the TYH microsatellite HUMTH01 in neuropathological conditions represents an example of approaches needed to validate genetic targets in the post-genomic era. (PMID:12428766)
• The ultrastsructural localization of this enzyme in human BPMCs is regulated by cell stimulation and related to the functional activity of the enzyme. (PMID:12457228)
• Tyrosine hydroxylase neurons constitute a subpopulation of non-pyramidal cells that are morphologically and neurochemically heterogenous. (PMID:12571119)
• Gene expression is a sensitive and semiquantitative marker for minimal residual disease detection of neuroblastoma (PMID:12576454)
• results support a direct function for tyrosine hydroxylase in the melanosome via a concerted action with tyrosinase to promote pigmentation. (PMID:12631248)
• This study does not support the involvement of tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders. (PMID:12782971)
• tyrosine hydroxylase deficiency results not in predominating dystonia, a largely nondegenerative condition, but in a progressive often lethal neurometabolic disorder, which can be improved but not cured by L-dopa (PMID:12891655)
• In summary, our results provide a novel regulatory frame in which modulation of chromatin structure by histone deacetylase may contribute to transcriptional regulation of the tyrosine hydroxylase. (PMID:14651963)
• These data suggest that the repressor element may play an important role in neuron cell-specific expression of the tyrosine hydroxylase gene. (PMID:14651989)
• tyrosine hydroxylase polymorphism is associated with Tobacco Use Disorder (PMID:15077008)
• the denatured state properties of the AAAHs (TH, TPH and PAH) contribute significantly to the stability of these enzymes and their tolerance towards missense mutations (PMID:15135070)
• Physiological effects of four mutations (T245P, T283M, R306H, T463M) in human TyrH that cause a mild form of DOPA-responsive dystonia are primarily due to the decreased stability of the mutant proteins rather than decreases in their intrinsic activities. (PMID:15468323)
• The mutation rate of TH gene in Chinese patients with AR-DRD is low, hence suggesting the genetic heterogeneity and a new locus for autosomal recessive dopa-responsive dystonia. (PMID:15476168)
• Val-81-Met polymorphism of tyrosine hydroxylase may have a role in early-onset alscoholism. (PMID:15722952)
• choroid contains abundant NPY and TH nerve fibers related to chroroidal vascular structures (PMID:15736042)
• Human TH minimal promoters may provide opportunity for selection of TH-positive human embryonic and adult stem cells for brain transplantation experiments in animal models for Parkinson’s disease. (PMID:15744773)
• High stability hTH1 mutants can be generated by the loss of a PEST motif in their N-termini and the structural change in the catalytic domain, which would promise an efficient production of dopamine in mammalian cells expressing N-terminus deleted hTH1. (PMID:15898085)
• The CpG-rich sequence located outside the 5’ promoter region of the human tyrosine hydroxylase (TH) gene appears to influence the functional effect of the adjacent intronic HUMTH01 microsatellite. (PMID:15953356)
• TH gene expression in neuronal progenitor cells does not depend on Nurr1 and a better understanding may have implications for the development of novel therapeutic approaches and the pathogenesis of neurological illnesses. (PMID:16252282)
• L-DOPA is produced by ectopically expressing tyrosine hydroxylase in mouse albino retinal pigment epithelium cells. (PMID:16445854)
• demonstrated that these cells possess tyrosinase as well as L-tyrosine hydroxylase (TH) activity and synthesize melanosomes (PMID:16447258)
• Presence is demonstrated, in normal adult mouse dorsal root ganglia, of a distinct subpopulation of tyrosine hydroxylase-positive, essentially calcitonin gene-related peptide (CGRP)- and isolectin B4 (IB4)-negative small/medium-sized neurons. (PMID:16516890)
• hierarchical phosphorylation provides a mechanism whereby the two major human TH isoforms (1 and 2) can be differentially regulated with only isoform 1 responding to the ERK pathway, whereas isoform 2 is more sensitive to calcium-mediated events (PMID:16644734)
• DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor (PMID:16731528)
• NRSF/REST functions as a repressor of TH transcription in NSCs via a mechanism dependent on the TH NRSE/RE1 sites. (PMID:16764822)
• The co-expression of GTP cyclohydrolase I (GCHI) with tyrosine hydroxylase (TH) indicates that TH is indeed active in human neurosecretory neurons. (PMID:17135716)
• In human chromaffin cells, activation of CRF1 receptors induced tyrosine hydroxylase, whereas activation of CRF2 suppressed it. (PMID:17194738)
• Chromatin remodeling might play a relevant role ine conferring tissue specific gene expression of the human tyrosine hydroxylate gene. (PMID:17195153)
• Results demonstrate for the first time existence of hTH isoforms Delta2,8,9 & Delta1b,2,8,9. Their general distribution in neuroblastoma and adrenal glands and translation into protein suggest a significant functional role for these novel hTH isoforms. (PMID:17391063)
• TH activity may be severely limited by oxygen availability even at moderate hypoxic conditions (PMID:17520326)
• Homozygous tyrosine hydroxylase gene promoter mutation is associated with encephalopathy (PMID:17698383)
• Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis at the rate-limiting step, TH. which may suggest new strategies to approach diagnosis and treatment of hypertension. (PMID:17698732)
• The extent of nestin-positive neuronal cells correlated with the appearance of tyrosine hydroxylase positive neurons. (PMID:17784840)
• TH allele tended towards association with higher severity of suicidal behaviour in bipolar patient. (PMID:17869399)
• Not all of the glomus cells in the carotid body express detectable TH levels either in normal or in some abnormal conditions (PMID:17926059)
• study does not support the involvement of tyrosine hydroxylase gene variants as major contributors to suicide, whereas dopa decarboxylase variants could mediate some features related to suicide and be involved in violent suicidal behavior (PMID:17948905)
• Tyrosine hydroxylase gene polymorphism is associated with gastric cancer (PMID:17972051)
• Reduced striatal tyrosine hydroxylase in incidental Lewy body disease. (PMID:17985144)
• The mRNA expression levels of IL-1beta, TNF-alpha and TH was higher in paranoid schizophrenic patients than those in normal controls. (PMID:17988588)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	th	ENSDARG00000030621
mus_musculus	Th	ENSMUSG00000000214
rattus_norvegicus	Th	ENSRNOG00000020410
drosophila_melanogaster	ple	FBGN0005626
caenorhabditis_elegans		WBGENE00000296

Paralogs (3): TPH1 (ENSG00000129167), TPH2 (ENSG00000139287), PAH (ENSG00000171759)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:98735) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 49 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased dopamine level	4
abnormal noradrenaline level	3
decreased body size	2
decreased locomotor activity	2
abnormal heart atrium morphology	2
dilated heart atrium	2
abnormal adrenaline level	2
dystonia	2
decreased heart rate	2
prenatal lethality, complete penetrance	2
embryonic lethality during organogenesis, incomplete penetrance	2
lethality throughout fetal growth and development, incomplete penetrance	2
blood vessel congestion	1
abnormal heart development	1
ventricular hypoplasia	1
weakness	1
atelectasis	1
decreased body weight	1
hyperactivity	1
impaired coordination	1
abnormal gait	1
abnormal cued conditioning behavior	1
abnormal motor coordination/balance	1
respiratory failure	1
abnormal associative learning	1

+24 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca mulatta	Q2HZ26	98.8%	Diamond
Oryctolagus cuniculus	P17290	95.5%	Diamond
Equus caballus	Q0EAB8	95.1%	Diamond
Bos taurus	Q2KIH7	92.5%	Diamond
Oncorhynchus mykiss	A0A060X6Z0	89.8%	Diamond
Anguilla anguilla	O42091	89.8%	Diamond
Canis lupus familiaris	Q76IQ3	88.3%	Diamond
Caenorhabditis briggsae	A8X3V8	88.1%	Diamond
Gallus gallus	P70080	88.1%	Diamond
Xenopus laevis	Q92142	88.1%	Diamond
Phasianidae sp.	P11982	78.9%	Diamond
Chromobacterium violaceum ATCC 12472	P30967	73.9%	Diamond
Ralstonia pseudosolanacearum GMI1000	Q8XU39	73.9%	Diamond
Pinus taeda	E5KBU3	69.8%	Diamond
Physcomitrium patens	E5KBU4	69.8%	Diamond
Caulobacter vibrioides CB15	Q9A7V7	63.4%	Diamond
Pseudomonas aeruginosa PAO1	P43334	59.3%	Diamond
Vibrio cholerae O1 biovar El Tor str. N16961	Q9KLB8	59.3%	Diamond
Chlamydomonas reinhardtii	A8HQD7	59.0%	Diamond
Schistosoma mansoni	O17446	56.1%	Diamond
Dictyostelium discoideum	Q54XS1	55.5%	Diamond
Mesorhizobium japonicum MAFF 303099	Q98D72	49.8%	Diamond
Streptomyces coeruleorubidus	F5BFC8	39.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TSPAN32	protein-coding	10077
C11orf21	protein-coding	29125
INS	protein-coding	3630
ASCL2	protein-coding	430
INS-IGF2	protein-coding	723961
MIR4686	ncRNA	100616126
IGF2	protein-coding	3481
IGF2-AS	ncRNA	51214
MIR675	ncRNA	100033819
LINC01219	ncRNA	104355220
H19	ncRNA	283120
MRPL23	protein-coding	6150
MIR483	ncRNA	619552

Protein

Protein identifiers

Tyrosine 3-monooxygenase — P07101 (reviewed: P07101)

Alternative names: Tyrosine 3-hydroxylase

All UniProt accessions (5): E7EQI0, P07101, F8W8M5, H0Y670, H0Y677

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, noradrenaline, and adrenaline. Uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to L-Dopa (PubMed:15287903, PubMed:1680128, PubMed:17391063, PubMed:24753243, PubMed:34922205, PubMed:8528210, Ref.18). In addition to tyrosine, is able to catalyze the hydroxylation of phenylalanine and tryptophan with lower specificity. Positively regulates the regression of retinal hyaloid vessels during postnatal development. Lacks catalytic activity. Lacks catalytic activity.

Subunit / interactions. Homotetramer (PubMed:24947669, Ref.18). Interacts (when phosphorylated at Ser-19) with YWHAG; one YWHAG dimer binds to one TH tetramer and this interaction may influence the phosphorylation and dephosphorylation of other sites. Interacts with NT5DC2; the interaction results in reduced phosphorylation and decreased catalytic activity of TH.

Subcellular location. Cytoplasm. Perinuclear region. Nucleus. Cell projection. Axon. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle.

Tissue specificity. Mainly expressed in the brain and adrenal glands.

Post-translational modifications. Phosphorylated on Ser-19, Ser-62 and Ser-71 by several protein kinases with different site specificities. Phosphorylation at Ser-62 and Ser-71 leads to an increase of TH activity. Phosphorylation at Ser-71 activates the enzyme and also counteracts the feedback inhibition of TH by catecholamines. Phosphorylation of Ser-19 and Ser-62 triggers the proteasomal degradation of TH through the ubiquitin-proteasome pathway. Phosphorylation at Ser-62 facilitates transport of TH from the soma to the nerve terminals via the microtubule network. Phosphorylation at Ser-19 induces the high-affinity binding to the 14-3-3 protein YWHAG; this interaction may influence the phosphorylation and dephosphorylation of other sites. Ser-19 increases the phosphorylation at Ser-71 in a hierarchical manner, leading to increased activity.

Disease relevance. Segawa syndrome autosomal recessive (ARSEGS) [MIM:605407] A form of DOPA-responsive dystonia presenting in infancy or early childhood. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Some cases present with parkinsonian symptoms in infancy. Unlike all other forms of dystonia, it is an eminently treatable condition, due to a favorable response to L-DOPA. The disease is caused by variants affecting the gene represented in this entry. May play a role in the pathogenesis of Parkinson disease (PD). A genome-wide copy number variation analysis has identified a 34 kilobase deletion over the TH gene in a PD patient but not in any controls.

Activity regulation. Inhibited in feedback fashion by the catecholamine neurotransmitters, especially by dopamine in competition with tetrahydrobiopterin. Phosphorylation of several Ser/Thr residues in the N-terminus regulates the catalytic activity. Ser-62 and Ser-71 are readily phosphorylated to activate the catalytic activity. A Cysteine modification induced by N-ethylmaleimide (NEM), inhibits tyrosine 3-monooxygenase activity through the modification of the Cys-207.

Pathway. Catecholamine biosynthesis; dopamine biosynthesis; dopamine from L-tyrosine: step 1/2.

Similarity. Belongs to the biopterin-dependent aromatic amino acid hydroxylase family.

Isoforms (6)

UniProt ID	Names	Canonical?
P07101-1	3, TH type 4	yes
P07101-2	1, TH type 3
P07101-3	2, HTH-1, hTH-Delta1b,2, TH type 1
P07101-4	4, hTH-Delta2, TH type 2
P07101-5	5, hTH-Delta2,8,9
P07101-6	6, hTH-Delta1b,2,8,9

RefSeq proteins (6): NP_000351, NP_001427464, NP_001427465, NP_001427466, NP_954986, NP_954987 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001273	ArAA_hydroxylase	Family
IPR005962	Tyr_3_mOase	Family
IPR018301	ArAA_hydroxylase_Fe/CU_BS	Binding_site
IPR019773	Tyrosine_3-monooxygenase-like	Family
IPR019774	Aromatic-AA_hydroxylase_C	Domain
IPR021164	Tyrosine_hydroxylase_CS	Conserved_site
IPR036329	Aro-AA_hydroxylase_C_sf	Homologous_superfamily
IPR036951	ArAA_hydroxylase_sf	Homologous_superfamily
IPR041903	Eu_TyrOH_cat	Domain
IPR045865	ACT-like_dom_sf	Homologous_superfamily
IPR049321	TH_ACT	Domain

Pfam: PF00351, PF12549, PF21417

Enzyme classification (BRENDA)

• EC 1.14.16.2 — tyrosine 3-monooxygenase (BRENDA: 49 organisms, 105 substrates, 117 inhibitors, 229 Km, 27 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-TYROSINE	0.001–2.39	74
TETRAHYDROBIOPTERIN	0.0041–0.507	38
(RS)-6-METHYL-5,6,7,8-TETRAHYDROPTERIN	0.023–0.051	20
TYROSINE	0.0061–0.5	19
L-PHENYLALANINE	0.0016–5	18
6,7-DIMETHYL-2-AMINO-4-HYDROXY-5,6,7,8-TETRAHYDO	0.0001–0.045	15
PHENYLALANINE	0.0013–0.3	8
TETRAHYDROPTERIN	0.01–0.63	6
6-METHYL-5,6,7,8-TETRAHYDROPTERIN	0.033–0.95	5
6-METHYLTETRAHYDROPTERIN	0.051–0.409	4
L-TYR	0.051–0.33	3
L-DOPA	0.056–0.146	2
2-AMINO-4-HYDROXY-6-METHYL-5,6,7,8-TETRAHYDROPTE	0.058	1
6,7-DIMETHYL-2-AMINO-4-HYDROXY-5,6,7,8-TETRAHYDR	0.34	1
6-METHYL-5,6,7,8-TETRAHYDROBIOPTERIN	0.15	1

Catalyzed reactions (Rhea)

• (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-tyrosine + O2 = (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin + L-dopa (RHEA:18201)

UniProt features (94 total): sequence variant 41, helix 18, strand 10, modified residue 4, splice variant 4, mutagenesis site 4, turn 4, binding site 3, sequence conflict 2, chain 1, region of interest 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

7 structures by resolution:

PDB	Title	Method	Resolution (Å)
2XSN	Crystal Structure of Human Tyrosine Hydroxylase Catalytic Domain	X-RAY DIFFRACTION	2.68
4J6S	14-3-3gamma complexed with the N-terminal sequence of tyrosine hydroxylase (residues 1-43)	X-RAY DIFFRACTION	3.08
6ZZU	Partial structure of the substrate-free tyrosine hydroxylase (apo-TH).	ELECTRON MICROSCOPY	3.5
6ZVP	Atomic model of the EM-based structure of the full-length tyrosine hydroxylase in complex …	ELECTRON MICROSCOPY	4
7A2G	Full-length structure of the substrate-free tyrosine hydroxylase (apo-TH).	ELECTRON MICROSCOPY	4.1
6ZN2	Partial structure of tyrosine hydroxylase in complex with dopamine showing the catalytic …	ELECTRON MICROSCOPY	4.3
7PIM	Partial structure of tyrosine hydroxylase lacking the first 35 residues in complex with …	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07101-F1	81.75	0.59

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Metabolic proteins, Predicted intracellular proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
455	important for substrate specificity

Ligand- & substrate-binding residues (3)

Position	Role
361	Fe cation
366	Fe cation
406	Fe cation

Post-translational modifications (4)

Type	Positions
Phosphoserine	502, 19, 62, 71

Mutagenesis-validated functional residues (4)

Position	Phenotype
62	affects subcellular localization. accumulates mainly in the soma of the neuroblastoma cells.
62	does not affect subcellular localization. distributed throughout the soma and neurites.
71	suppresses feedback inhibition induced by dopamine. suppresses feedback inhibition induced by dopamine; when associated with a-207.
207	suppresses the decrease in tyrosine 3-monooxygenase activity induced by nem modification. suppresses feedback inhibition induced by …

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-209905	Catecholamine biosynthesis	curated
R-HSA-1430728	Metabolism	—
R-HSA-209776	Metabolism of amine-derived hormones	—
R-HSA-71291	Metabolism of amino acids and derivatives	—

MSigDB gene sets: 266 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, ATF_B, GOBP_MEMORY, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_ETHANOL, GOBP_COGNITION, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_BEHAVIOR, HARRIS_HYPOXIA, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_NEUROGENESIS, CREBP1_Q2, GOBP_CELL_CELL_SIGNALING

GO Biological Process (25): response to hypoxia (GO:0001666), synaptic transmission, dopaminergic (GO:0001963), heart morphogenesis (GO:0003007), dopamine biosynthetic process from tyrosine (GO:0006585), heart development (GO:0007507), visual perception (GO:0007601), learning (GO:0007612), memory (GO:0007613), mating behavior (GO:0007617), locomotory behavior (GO:0007626), regulation of heart contraction (GO:0008016), anatomical structure morphogenesis (GO:0009653), animal organ morphogenesis (GO:0009887), dopamine biosynthetic process (GO:0042416), epinephrine biosynthetic process (GO:0042418), norepinephrine biosynthetic process (GO:0042421), serotonin biosynthetic process (GO:0042427), eye photoreceptor cell development (GO:0042462), pigmentation (GO:0043473), response to ethanol (GO:0045471), embryonic camera-type eye morphogenesis (GO:0048596), cognition (GO:0050890), hyaloid vascular plexus regression (GO:1990384), aromatic amino acid metabolic process (GO:0009072), catecholamine biosynthetic process (GO:0042423)

GO Molecular Function (9): tyrosine 3-monooxygenase activity (GO:0004511), iron ion binding (GO:0005506), enzyme binding (GO:0019899), identical protein binding (GO:0042802), monooxygenase activity (GO:0004497), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen (GO:0016714), metal ion binding (GO:0046872)

GO Cellular Component (12): nucleus (GO:0005634), cytoplasm (GO:0005737), smooth endoplasmic reticulum (GO:0005790), cytosol (GO:0005829), synaptic vesicle (GO:0008021), cytoplasmic side of plasma membrane (GO:0009898), axon (GO:0030424), cytoplasmic vesicle (GO:0031410), melanosome membrane (GO:0033162), neuron projection (GO:0043005), perikaryon (GO:0043204), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Metabolism of amine-derived hormones	1
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

54 GO namespaces:

Category	Terms
cellular anatomical structure	4
catecholamine biosynthetic process	3
cytoplasm	3
animal organ development	2
learning or memory	2
protein binding	2
response to stress	1
response to decreased oxygen levels	1
chemical synaptic transmission	1
heart development	1
animal organ morphogenesis	1
dopamine biosynthetic process	1
circulatory system development	1
sensory perception of light stimulus	1
reproductive behavior	1
behavior	1
heart contraction	1
regulation of blood circulation	1
developmental process	1
anatomical structure development	1
anatomical structure morphogenesis	1
dopamine metabolic process	1
epinephrine metabolic process	1
norepinephrine metabolic process	1
serotonin metabolic process	1
indole-containing compound biosynthetic process	1
phenol-containing compound biosynthetic process	1
primary amino compound biosynthetic process	1
eye photoreceptor cell differentiation	1
photoreceptor cell development	1
biological_process	1
response to alcohol	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen	1
transition metal ion binding	1
oxidoreductase activity	1
binding	1
catalytic activity	1
monooxygenase activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
endoplasmic reticulum	1
exocytic vesicle	1
presynapse	1
plasma membrane	1
cytoplasmic side of membrane	1
neuron projection	1
intracellular vesicle	1
melanosome	1
chitosome	1
pigment granule membrane	1
plasma membrane bounded cell projection	1
neuronal cell body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 15 of 46 annotations. The rest are phylogenetic / computational / electronic (IEA).

15 experimentally-supported GO terms:

GO term	NS	Evidence
dopamine biosynthetic process	BP	direct assay
epinephrine biosynthetic process	BP	direct assay
norepinephrine biosynthetic process	BP	direct assay
response to ethanol	BP	direct assay
response to hypoxia	BP	direct assay
cytoplasm	CC	direct assay
cytoplasmic side of plasma membrane	CC	direct assay
cytoplasmic vesicle	CC	direct assay
melanosome membrane	CC	direct assay
neuron projection	CC	direct assay
nucleus	CC	direct assay
smooth endoplasmic reticulum	CC	direct assay
enzyme binding	MF	physical interaction
identical protein binding	MF	physical interaction
tyrosine 3-monooxygenase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 3,006 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TH	DBH	P09172	971
TH	DDC	P20711	944
TH	PNMT	P11086	942
TH	SLC6A3	Q01959	939
TH	SLC18A2	Q05940	876
TH	SNCA	P37840	871
TH	GCH1	P30793	861
TH	CHAT	P28329	860
TH	DRD2	P14416	835
TH	GDNF	P39905	835
TH	BDNF	P23560	831
TH	NR4A2	P43354	824
TH	CALB2	P22676	811
TH	NGF	P01138	806
TH	NPY	P01303	802

IntAct

Human interaction partners of TH in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

4 partners by confidence:

Partner	Interaction type	MIscore	Records
YWHAZ	association	0.530	4
MAP3K7	association	0.350	1
YWHAG	association	0.350	1
YWHAH	association	0.350	1

BioGRID (42 interactions; top human partners by supporting records): NFIC (Affinity Capture-MS; 3 records), DNAJC12 (Affinity Capture-MS; 2 records), KDM3B (Affinity Capture-MS; 2 records), MAP3K7 (Affinity Capture-MS; 2 records), MTFR2 (Affinity Capture-MS; 2 records), RELL1 (Affinity Capture-MS; 2 records), TAOK2 (Affinity Capture-MS; 2 records), ZBTB34 (Affinity Capture-MS; 2 records), BAHCC1 (Cross-Linking-MS (XL-MS)), CRABP1 (Two-hybrid), CREBBP (Co-localization), CUL3 (Affinity Capture-MS), CUL4A (Affinity Capture-MS), DAAM2 (Two-hybrid), EEA1 (Cross-Linking-MS (XL-MS))

SIGNOR signaling

showing 19 of 23 signaling interactions:

A	Effect	B	Mechanism
CAMK2A	up-regulates	TH	phosphorylation
“MTA1/DJ1 complex”	“up-regulates quantity by expression”	TH	“transcriptional regulation”
CTF1	“down-regulates quantity by repression”	TH	“transcriptional regulation”
TH	“down-regulates quantity”	tyrosine	“chemical modification”
TH	“up-regulates quantity”	L-dopa	“chemical modification”
Gbeta	up-regulates	TH	phosphorylation
ERK1/2	up-regulates	TH	phosphorylation
CDK5	“up-regulates activity”	TH	phosphorylation
MAPK1	up-regulates	TH	phosphorylation
MAPK3	up-regulates	TH	phosphorylation
RPS6KA3	up-regulates	TH	phosphorylation
MAPKAPK5	up-regulates	TH	phosphorylation
RPS6KA5	up-regulates	TH	phosphorylation
ARNT	“down-regulates quantity by repression”	TH	“transcriptional regulation”
NPAS1	“down-regulates quantity by repression”	TH	“transcriptional regulation”
PRKACA	“up-regulates activity”	TH	phosphorylation
MAPKAPK2	“up-regulates activity”	TH	phosphorylation
CAMK2G	“up-regulates activity”	TH	phosphorylation
SFPQ	“down-regulates quantity by repression”	TH	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for TH: 1,249 ClinVar records (169 pathogenic / likely pathogenic); 4 PharmGKB clinical annotations; 17 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,249 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	117
Uncertain significance	387
Likely benign	552
Benign	41

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 169 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
12327	NM_000360.4(TH):c.605G>A (p.Arg202His)	Pathogenic	criteria provided, multiple submitters, no conflicts	20
188890	NM_000360.4(TH):c.1282C>T (p.Gln428Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
449110	NM_000360.4(TH):c.364C>T (p.Arg122Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
371630	NM_000360.4(TH):c.601C>T (p.Gln201Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
521707	NM_000360.4(TH):c.672C>G (p.Tyr224Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
691995	NM_000360.4(TH):c.448C>T (p.Gln150Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1068293	NM_000360.4(TH):c.488-1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	2
554554	NM_000360.4(TH):c.91-818G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
555292	NM_000360.4(TH):c.90+13G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
557031	NM_000360.4(TH):c.644+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
640660	NM_000360.4(TH):c.604C>T (p.Arg202Cys)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
1913004	NM_000360.4(TH):c.1032C>G (p.Phe344Leu)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
12334	NM_000360.4(TH):c.983G>T (p.Cys328Phe)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
370745	NM_000360.4(TH):c.977+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
554683	NM_000360.4(TH):c.90+13G>T	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3

Per-variant reference — Sugi Variant

Explore TH’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 1,241):

Position(s)	Effect	Δscore	Sites
11:2164393–2164394	acceptor_loss	1.0000	5
11:2165230–2165231	donor_loss	1.0000	5
11:2165764	acceptor_loss	1.0000
11:2166000–2166001	donor_loss	1.0000	5
11:2166479	donor_loss	1.0000
11:2168089–2168090	donor_loss	1.0000	4
11:2168181	acceptor_gain	1.0000
11:2168188	acceptor_gain	1.0000
11:2168667	acceptor_gain	1.0000
11:2168682	acceptor_gain	1.0000

AlphaMissense

1,204 missense substitutions predicted likely pathogenic (of 3,205 scored), across 296 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H361	8	0.997	0.999
H366	8	0.997	0.999
D358	8	0.996	0.999
F339	8	0.994	0.999
H222	8	0.993	0.999
F330	8	0.993	1.000
D329	8	0.989	0.996
D455	8	0.989	0.997
H347	8	0.987	0.998
D227	8	0.961	0.988
F443	8	0.950	0.993
D75	8	0.946	0.979
F316	8	0.940	0.998
D205	8	0.934	0.983
H353	8	0.934	0.995
F375	8	0.919	0.993
H143	8	0.902	0.981
D219	8	0.901	0.939
F378	8	0.899	0.993
S71	8	0.871	0.981

HPA cancer prognostics

RNA cancer specificity: Group enriched (Bladder Urothelial Carcinoma, Head and Neck Squamous Cell Carcinoma)

Disease associations

OMIM: gene MIM:191290 | disease phenotypes: MIM:605407, MIM:210370, MIM:128230

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
TH-deficient dopa-responsive dystonia	Definitive	Autosomal recessive	4
tyrosine hydroxylase deficiency	Definitive	Autosomal recessive	3

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
tyrosine hydroxylase deficiency	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (12 panels, 11 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

12 panels:

Panel	Rating
DDG2P	green
Dystonia, chorea or related movement disorder, childhood onset	green
Early onset dystonia	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Neurotransmitter disorders	green
Paediatric disorders	green
Parkinson Disease and Complex Parkinsonism	green
Unexplained death in infancy and sudden unexplained death in childhood	green
Undiagnosed metabolic disorders	amber

Mondo (5): TH-deficient dopa-responsive dystonia (MONDO:0011551), Bietti crystalline corneoretinal dystrophy (MONDO:0008865), dystonic disorder (MONDO:0003441), dystonia 5 (MONDO:0007495), tyrosine hydroxylase deficiency (MONDO:0100064)

Orphanet (3): Autosomal recessive dopa-responsive dystonia (Orphanet:101150), Bietti crystalline dystrophy (Orphanet:41751), Autosomal dominant dopa-responsive dystonia (Orphanet:98808)

HPO phenotypes

40 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000298	Mask-like facies
HP:0000508	Ptosis
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001256	Mild intellectual disability
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001300	Parkinsonism
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001348	Brisk reflexes
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0001945	Fever
HP:0002019	Constipation
HP:0002063	Rigidity
HP:0002066	Gait ataxia
HP:0002067	Bradykinesia
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002174	Postural tremor
HP:0002375	Hypokinesia
HP:0002395	Lower limb hyperreflexia
HP:0002448	Progressive encephalopathy
HP:0002451	Limb dystonia
HP:0002548	Parkinsonism with favorable response to dopaminergic medication
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0003781	Excessive salivation
HP:0003785	Decreased CSF homovanillic acid concentration
HP:0003828	Variable expressivity
HP:0004373	Focal dystonia
HP:0007325	Generalized dystonia
HP:0008936	Axial hypotonia
HP:0010553	Oculogyric crisis
HP:0011968	Feeding difficulties
HP:0030166	Night sweats

GWAS associations

17 associations:

Study	Trait	p-value
GCST008839_540	Height	6e-35
GCST000488_11	Prostate cancer	3e-33
GCST90002384_301	Hemoglobin	7e-14
GCST90002383_523	Hematocrit	9e-13
GCST011369_18	Iron status biomarkers (ferritin levels)	3e-11
GCST002413_2	Prostate cancer (early onset)	2e-8
GCST008464_3	Type 2 diabetes	2e-8
GCST002560_9	Type 2 diabetes	1e-7
GCST006197_5	Type 1 diabetes autoantibodies in high risk HLA genotype individuals (time to event)	1e-7
GCST006196_1	Type 1 diabetes in high risk HLA genotype individuals (time to event)	3e-7
GCST90026412_2	Severe autoimmune type 2 diabetes	3e-7
GCST001370_26	Prostate cancer (SNP x SNP interaction)	3e-6
GCST001370_13	Prostate cancer (SNP x SNP interaction)	4e-6
GCST001370_14	Prostate cancer (SNP x SNP interaction)	4e-6
GCST001370_28	Prostate cancer (SNP x SNP interaction)	4e-6
GCST006197_8	Type 1 diabetes autoantibodies in high risk HLA genotype individuals (time to event)	6e-6
GCST002112_1	Celiac disease	7e-6

EFO canonical traits (from GWAS)

6 canonical traits:

EFO ID	Trait name
EFO:0000409	disease free survival
EFO:0000482	event free survival time
EFO:0004866	autoantibody measurement
EFO:0004459	ferritin measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D020821	Dystonic Disorders	C10.228.662.300
C535440	Bietti Crystalline Dystrophy *(supp.)*
C537537	Segawa syndrome, autosomal recessive *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1969 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the TH protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
METYROSINE	Small molecule	4

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

4 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs10770140	Toxicity	3	opioids	Opioid-Related Disorders
rs10770141	Toxicity	3	opioids	Opioid-Related Disorders
rs2070762	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity
rs2070762	Toxicity	3	opioids	Opioid-Related Disorders

PharmGKB variants

3 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10770141	TH	3	3.00	1	opioids
rs2070762	TH	3	3.50	2	methylphenidate;opioids
rs10770140	TH	3	3.00	1	opioids

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

4 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs2070762	opioids	Toxicity	Allele G is associated with increased risk of Opioid-Related Disorders when exposed to opioids as compared to allele A.	PMID:29210332
rs2070762	methylphenidate	Efficacy	Genotype GG is associated with decreased response to methylphenidate in children with Attention Deficit Disorder with Hyperactivity as compared to genotypes AA + AG.	PMID:26810137
rs10770141	opioids	Toxicity	Genotypes AA + AG is associated with increased risk of Opioid-Related Disorders due to opioids as compared to genotype GG.	PMID:32232669
rs10770140	opioids	Toxicity	Genotypes CT + TT are associated with increased risk of Opioid-Related Disorders due to opioids as compared to genotype CC.	PMID:32232669

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Amino acid hydroxylases

Binding affinities (BindingDB)

2 measured of 2 human assays (4 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
(R)-10,11-Dihydroxy-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolinium	EC50	1.1 nM
NPA-11-OH-R,(+)	KI	45 nM

ChEMBL bioactivities

3 potent at pChembl≥5 of 5 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.52	IC50	300	nM	R-N-PROPYLNORAPOMORPHINE
6.14	IC50	720	nM	IOTYROSINE
6.00	IC50	1000	nM	CHEMBL330274

PubChem BioAssay actives

3 with measured affinity, of 9 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(6aR)-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol	313108: Inhibition of tyrosine hydroxylase	ic50	0.3000	uM
(2S)-2-amino-3-(4-hydroxy-3-iodophenyl)propanoic acid	340328: Inhibition of tyrosine hydroxylase	ic50	0.7200	uM
(6aS)-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol	313108: Inhibition of tyrosine hydroxylase	ic50	1.0000	uM

CTD chemical–gene interactions

59 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	affects reaction, increases expression, decreases reaction, affects cotreatment, decreases expression	11
Estradiol	affects expression, increases reaction, increases expression, increases secretion	4
1-Methyl-4-phenylpyridinium	increases expression, decreases reaction, decreases expression	4
Paraquat	decreases reaction, increases expression	3
Benzo(a)pyrene	affects methylation, increases expression	2
Chlorpyrifos	affects reaction, increases expression, decreases expression	2
Methamphetamine	decreases reaction, affects reaction, decreases activity, decreases expression	2
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine	decreases expression, decreases reaction	2
propionaldehyde	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression, decreases reaction	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
decamethrin	decreases expression	1
butyraldehyde	increases expression	1
nickel chloride	decreases reaction, increases expression	1
manganese chloride	increases methylation, decreases expression	1
aflatoxin B2	decreases methylation	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression, decreases reaction	1
pentanal	decreases expression	1
ginsenoside Re	decreases activity, decreases expression, decreases reaction	1
methyllycaconitine	affects binding, decreases activity, decreases reaction, increases expression	1
fipronil	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
prothioconazole	increases expression	1
(+)-JQ1 compound	decreases expression	1
ortho-topolin riboside	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3777462	Binding	Binding affinity to tyrosine hydroxylase (unknown origin) at 10 uM	Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies. — *Eur J Med Chem*

Cellosaurus cell lines

6 cell lines: 4 induced pluripotent stem cell, 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5F78	SVG-TH	Transformed cell line	Male
CVCL_A8IB	ESi101-A	Induced pluripotent stem cell	Female
CVCL_A8IC	ESi102-A	Induced pluripotent stem cell	Female
CVCL_D1UL	Abcam U-87MG TH KO	Cancer cell line	Male
CVCL_D4ZP	SDQLCHi066-A	Induced pluripotent stem cell	Female
CVCL_UM01	DHMCi001-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00000374	Phase 4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	Phase 4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	Phase 4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	Phase 4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	Phase 4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	Phase 4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	Phase 4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	Phase 4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	Phase 4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	Phase 4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	Phase 4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	Phase 4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	Phase 4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	Phase 4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	Phase 4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	Phase 4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	Phase 4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	Phase 4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	Phase 4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	Phase 4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	Phase 4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	Phase 4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	Phase 4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	Phase 4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	Phase 4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	Phase 4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	Phase 4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	Phase 4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	Phase 4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	Phase 4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	Phase 4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	Phase 4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	Phase 4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	Phase 4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	Phase 4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	Phase 4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	Phase 4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	Phase 4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	Phase 4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	Phase 4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety
NCT00177580	Phase 4	COMPLETED	Improving Symptoms of Schizophrenia and Schizoaffective Disorder by Supplementing Medications With Pravastatin
NCT00182442	Phase 4	COMPLETED	Cognition, Functioning and Quality of Life
NCT00182494	Phase 4	UNKNOWN	Diabetes Prevention Program in Schizophrenia [DPPS]
NCT00183625	Phase 4	COMPLETED	Supported Employment and Skills Training in Conjunction With Pharmacotherapy in Schizophrenia Patients
NCT00186771	Phase 4	UNKNOWN	Magnetic Stimulation as a Treatment for Auditory Hallucinations in Schizophrenia
NCT00190749	Phase 4	COMPLETED	Safety Study of Olanzapine and a Comparator in Patients With Schizophrenia and Schizoaffective Disorder
NCT00191555	Phase 4	COMPLETED	Efficacy Study of Switching Stabilized Schizophrenic Patients From Conventional to Atypical Antipsychotic Treatment
NCT00194025	Phase 4	COMPLETED	Valproate in Late Life Schizophrenia
NCT00199940	Phase 4	COMPLETED	Safety And Efficacy Study Of Ziprasidone In Pediatric Psychotic Illness
NCT00202306	Phase 4	COMPLETED	Indicated Prevention of Psychotic Disorders With Low-dose Lithium
NCT00203788	Phase 4	COMPLETED	Improving Work Outcome in People With Recent-onset Schizophrenia
NCT00204061	Phase 4	COMPLETED	Early Pharmacological and Psychological Intervention for Late Prodromal States of Psychosis
NCT00205660	Phase 4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00206102	Phase 4	COMPLETED	A Study of the Cataractogenic Potential of Seroquel and Risperdal in the Treatment of Participants With Schizophrenia or Schizoaffective Disorder
NCT00208143	Phase 4	COMPLETED	Seroquel Therapy for Substance Use Disorders Comorbid With Schizophrenia
NCT00208169	Phase 4	COMPLETED	Abilify Therapy for Reducing Comorbid Substance Abuse
NCT00214578	Phase 4	COMPLETED	Seroquel on Glucose Metabolism
NCT00215579	Phase 4	COMPLETED	Determining the Effects of Risperdal Consta in Patients With Psychotic Disorders and Incomplete Adherence
NCT00216528	Phase 4	COMPLETED	A Study to Evaluate Symptomatic Remission in Schizophrenia With Long Acting Risperidone Microspheres
NCT00216632	Phase 4	COMPLETED	A Study of Treatment Success in Changing From Olanzapine to Long-acting Injectable Risperidone (RISPERDAL® CONSTA™)

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for TH across ~30M SureChEMBL compounds — explore on Sugi Predict.