TH

protein-coding

tyrosine hydroxylase

Gene summary

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. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000360.4

Inheritance

ClinVar variants

P:194U:320B:341

Top phenotype

Segawa syndrome, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr11:2,163,929-2,171,815

External References & Databases

Ensembl (ENSG00000180176)

Transcript & Mutation Effects

hg38 • Region Span ~7.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

TH-deficient dopa-responsive dystoniaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011551

Submitter: Ambry Genetics

tyrosine hydroxylase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100064

Submitter: Natera

tyrosine hydroxylase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100064

Submitter: ClinGen

The relationship between TH and tyrosine hydroxylase deficiency, an autosomal recessive disorder of tyrosine metabolism, was evaluated using the ClinGen Clinical Validity Framework as of March 8th, 2019. Variants in TH were first reported in humans with this disorder in 1995 (Lüdecke et al, PMID 7814018). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Fourteen unique variants were curated (missense, nonsense, frameshift, intronic, and promoter) in 15 probands from 14 publications (Lüdecke et al, 1995, PMID 7814018; van den Heuvel et al, 1998, PMID 9703425; Janssen et al, 2000, PMID 11281275; Swaans et al, 2000, PMID 11246459; Furukawa et al, 2001, PMID 11160968; Hoffmann et al, 2003, PMID 12891655; Ribasés et al, 2007, PMID 17698383; Verbeek et al, 207, PMID 17696123; Pons et al, 2010, PMID 20198643; Ormazabal et al, 2011, PMID 21465550; Chi et al, 2012, PMID 22264700; Goswami et al, 2017, PMID 28667724; Katus et al, 2017, PMID 29225908; Feng et al, 2018, PMID 30383639). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of TH, which catalyzes the conversion of L-tyrosine to L-dopa (Nagatsu et al, 1964, PMID 5836553), functional studies (Fossbakk et al, 2014, PMID 24753243) and the biochemical features and clinical features of mouse models (Kobayashi et al, 1995, PMID 7592982; Korner et al, 2015, PMID 26276013). In summary, TH is definitively associated with TH deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel. This curation includes data collected by Counsyl.

TH-deficient dopa-responsive dystoniaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011551

Submitter: Orphanet

TH-deficient dopa-responsive dystoniaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011551

Submitter: G2P

tyrosine hydroxylase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100064

Submitter: Myriad Women's Health

TH-deficient dopa-responsive dystoniaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011551

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Segawa syndrome, autosomal recessiveAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: The condition can have infantile onset, and treatment (eg, with L-dopa alone or combined with other medications), can be effective, though has not been reported to be universally so

Refs: 7814018; 8817341; 9732974; 10407773; 10585338; 11196107; 16049992; 17696123; 10753262; 11246459; 11241071; 11134401; 11921123; 12891655; 14705130; 15505183; 18058633; 19282209; 20056467; 20301610; 21937992; 21940685; 22264700; 22691284; 22815559; 23389938

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TH variants in ClinVar

12 Conditions Cataloged

Autosomal recessive DOPA responsive dystoniaTotal: 1114

not providedTotal: 166

Inborn genetic diseasesTotal: 87

not specifiedTotal: 39

TH-related disorderTotal: 19

Dystonic disorderTotal: 3

Intellectual disabilityTotal: 2

Neonatal insulin-dependent diabetes mellitusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000360.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	323 clinvar	5 clinvar	337
missense	2 clinvar	52 clinvar	309 clinvar	12 clinvar	1 clinvar	376
nonsense	14 clinvar	18 clinvar				32
start loss			1 clinvar			1
frameshift	24 clinvar	43 clinvar				67
splice donor/acceptor (+/-2bp)	2 clinvar	39 clinvar	1 clinvar			42
Total	42	152	320	335	6	855

Highest pathogenic variant AF is 0.00014401547

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000360.4	RefSeq	NP_000351.2	13	MANE Select
ENST00000352909.8	Ensembl	ENSP00000325951.4	13	MANE Select
NM_001440535.1	RefSeq	NP_001427464.1	13	Standard
NM_001440536.1	RefSeq	NP_001427465.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
th	Danio rerio	Structure: head Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

Danio rerio

Structure: head

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Folate biosynthesis - Homo sapiens (human)
Dopaminergic synapse - Homo sapiens (human)
Amphetamine addiction - Homo sapiens (human)
Prolactin signaling pathway - Homo sapiens (human)
Parkinson,s disease - Homo sapiens (human)

Biological Process

response to hypoxia
synaptic transmission, dopaminergic
response to amphetamine
heart morphogenesis
dopamine biosynthetic process from tyrosine

Molecular Function

tyrosine 3-monooxygenase activity
protein binding
ferrous iron binding
ferric iron binding
amino acid binding

Cellular Component

nucleus
cytoplasm
mitochondrion
smooth endoplasmic reticulum
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381178
Coding exons: 14
Length: 7949
Individuals with no LoFs: 125563
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125602
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.564	321	351	0.915	0.0000246	3327
Missense (PolyPhen)		106	142.71	0.74276		1390
Synonymous	-0.191	160	157	1.02	0.0000117	1093
Loss of Function	2.42	14	27.8	0.504	0.00000146	298

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00099	0.00098	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000093	0.000088	rare
South Asian	0.000070	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in the physiology of adrenergic neurons.;
Disease: DISEASE: Note=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. {ECO:0000269|PubMed:20809526}.;

Recessive Scores

pRec: 0.855

Intolerance Scores

LoFtool: 0.0190
RVIS EVS: -0.95
RVIS percentile EVS: 9.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.975

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium