Tyrosine hydroxylase deficiency

Summary

Tyrosine hydroxylase deficiency (MONDO:0100064) is a disease caused by TH (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TH (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	tyrosine hydroxylase deficiency
Mondo ID	MONDO:0100064
MeSH	C537537
ICD-11	247698609
NCIT	C157158
UMLS	C5700309
MedGen	1814581
GARD	0026032
Is cancer (heuristic)	no

Also known as: TH deficiency · tyrosine 3-monooxygenase deficiency · tyrosine Hydroxylase deficiency · tyrosine hydroxylase deficiency

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records · 4 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of biogenic amine metabolism and transport › inborn disorder of neurotransmitter metabolism and transport › tyrosine hydroxylase deficiency

Related subtypes (3): Brunner syndrome, disorder of catecholamine synthesis, brain dopamine-serotonin vesicular transport disease

Subtypes (3): TH-deficient dopa-responsive dystonia, TH-deficient infantile parkinsonism and motor delay, TH-deficient progressive infantile encephalopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
948892	NM_000360.4(TH):c.646G>A (p.Gly216Ser)	TH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TH	Definitive	Autosomal recessive	tyrosine hydroxylase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TH	Orphanet:101150	Autosomal recessive dopa-responsive dystonia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TH	HGNC:11782	ENSG00000180176	P07101	Tyrosine 3-monooxygenase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TH	Tyrosine 3-monooxygenase	Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, noradrenaline, and adrenaline.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TH	Enzyme (other)	yes	1.14.16.2	ArAA_hydroxylase, Tyr_3_mOase, ArAA_hydroxylase_Fe/CU_BS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TH	147	tissue_specific	marker	substantia nigra pars reticulata, substantia nigra pars compacta, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TH	3,526

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TH	P07101	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Catecholamine biosynthesis	1	2855.0×	4e-04	TH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dopamine biosynthetic process from tyrosine	1	16852.0×	0.001	TH
epinephrine biosynthetic process	1	8426.0×	0.001	TH
serotonin biosynthetic process	1	4213.0×	0.002	TH
mating behavior	1	2808.7×	0.002	TH
hyaloid vascular plexus regression	1	2407.4×	0.002	TH
synaptic transmission, dopaminergic	1	2106.5×	0.002	TH
norepinephrine biosynthetic process	1	2106.5×	0.002	TH
dopamine biosynthetic process	1	1872.4×	0.002	TH
embryonic camera-type eye morphogenesis	1	1123.5×	0.002	TH
eye photoreceptor cell development	1	842.6×	0.003	TH
pigmentation	1	702.2×	0.003	TH
eating behavior	1	601.9×	0.003	TH
regulation of heart contraction	1	495.6×	0.004	TH
heart morphogenesis	1	374.5×	0.005	TH
cognition	1	285.6×	0.005	TH
learning	1	280.9×	0.005	TH
animal organ morphogenesis	1	191.5×	0.007	TH
memory	1	183.2×	0.007	TH
locomotory behavior	1	179.3×	0.007	TH
response to ethanol	1	146.5×	0.008	TH
anatomical structure morphogenesis	1	139.3×	0.008	TH
response to hypoxia	1	95.8×	0.011	TH
visual perception	1	79.5×	0.013	TH
heart development	1	78.8×	0.013	TH

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TH	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TH	1.14.16.2	tyrosine 3-monooxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TH	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.