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TH
tyrosine hydroxylase
TH is located on the short (p) arm of chromosome 11, at band 11p15.5. Arm ratio per GRCh38 - banding schematic.
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Overview
The TH gene encodes tyrosine hydroxylase, a critical enzyme in the synthesis of catecholamines - a group of chemical messengers that includes dopamine, norepinephrine, and epinephrine. These neurotransmitters play essential roles in both the central and autonomic nervous systems, controlling voluntary movement, emotional responses, and involuntary processes such as blood pressure regulation and body temperature maintenance.
Variants in TH are inherited in an autosomal recessive pattern, meaning that individuals require pathogenic changes in both copies of the gene to develop associated conditions. The primary condition linked to TH variants is tyrosine hydroxylase deficiency, a movement disorder that can range from mild to severe. Understanding how changes in this gene affect catecholamine production helps explain the neurological symptoms observed in affected individuals.
What the gene does
Tyrosine hydroxylase functions as the rate-limiting enzyme in catecholamine biosynthesis, controlling the speed at which these crucial neurotransmitters are produced. The enzyme catalyses the hydroxylation of the amino acid tyrosine to form L-DOPA (levodopa), which serves as the precursor for all catecholamines. This initial conversion represents the critical control point in the entire pathway.
Once L-DOPA is formed, it can be converted to dopamine through the action of another enzyme. Dopamine itself can then be further modified to produce norepinephrine and epinephrine. These catecholamines are released throughout the nervous system, transmitting signals between nerve cells and from nerve cells to other tissues. They are particularly important in regions of the brain that coordinate movement, regulate mood, and respond to stress. The autonomic nervous system relies heavily on catecholamines to modulate involuntary functions, releasing these molecules in response to physical or emotional challenges.
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Chromosome location
The TH gene is located on the short arm of chromosome 11 at position 15.5, designated as 11p15.5. This chromosomal region contains several other genes involved in metabolism and cellular regulation. The precise genomic location of TH places it in a gene-dense area of the genome, though the gene itself functions independently of its chromosomal neighbours in catecholamine synthesis.
Protein structure
The tyrosine hydroxylase protein comprises 528 amino acids and contains a disordered region spanning amino acids 33 to 65. Disordered regions in proteins lack fixed three-dimensional structure and often play roles in regulatory interactions, allowing the protein to bind to multiple partners or respond to cellular signals. This structural flexibility in the N-terminal portion of tyrosine hydroxylase may contribute to the enzyme's regulation, as tyrosine hydroxylase activity is tightly controlled through multiple mechanisms including phosphorylation and feedback inhibition by catecholamines.
Key variants
Pathogenic variants in TH reduce the catalytic activity of tyrosine hydroxylase, limiting the cell's ability to produce adequate quantities of L-DOPA and downstream catecholamines. The severity of the resulting condition often correlates with the degree of residual enzyme activity. Some variants abolish enzyme function almost entirely, whilst others permit partial activity. Because TH-related conditions follow autosomal recessive inheritance, carriers with one pathogenic variant and one functional copy typically produce sufficient enzyme activity to maintain normal catecholamine levels.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Variants in the TH gene cause tyrosine hydroxylase deficiency, a condition primarily affecting movement and neurological function. The clinical presentation varies considerably depending on the specific variants involved and the resulting level of enzyme activity. Individuals with more severe enzyme deficiency may experience early-onset movement abnormalities, developmental delays, and autonomic dysfunction, whilst those with milder forms may present with dystonia and tremor that respond well to L-DOPA treatment. The spectrum of severity reflects the range of biochemical impairment caused by different TH variants.
- Tyrosine hydroxylase deficiency Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic TH variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The TH gene appears on multiple NHS Genomic Medicine Service gene panels, reflecting its recognised clinical importance. It holds green (high evidence) classification on panels including Childhood onset dystonia, chorea or related movement disorder, Early onset dystonia, Neurotransmitter disorders, and Parkinson Disease and Complex Parkinsonism. The gene is also included in the Intellectual disability panel and the Likely inborn error of metabolism panel. This extensive panel coverage indicates that TH testing is recommended for patients presenting with these clinical features within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between a carrier and someone affected by TH-related conditions?
A carrier has one pathogenic TH variant and one functional copy, typically producing enough tyrosine hydroxylase to maintain normal catecholamine levels without symptoms. An affected individual inherits pathogenic variants in both copies of TH, resulting in insufficient enzyme activity and the neurological features of tyrosine hydroxylase deficiency.
Why does L-DOPA treatment help some individuals with TH variants?
L-DOPA treatment bypasses the impaired tyrosine hydroxylase step by directly providing the product that the enzyme would normally create. This allows cells to produce dopamine and other catecholamines even when tyrosine hydroxylase activity is reduced, though the effectiveness depends on the severity of enzyme deficiency and the function of downstream enzymes.
Are TH variants common in the general population?
Tyrosine hydroxylase deficiency is a rare autosomal recessive condition, meaning that whilst carrier status occurs in the population, it is uncommon. The exact carrier frequency varies across different populations and is not as well characterised as for more prevalent genetic conditions.
References
- Pearl PL, Taylor JL, Trzcinski S. The pediatric neurotransmitter disorders. Journal of child neurology. 2007. PMID: 17690069
- Pearl PL, Capp PK, Novotny EJ. Inherited disorders of neurotransmitters in children and adults. Clinical biochemistry. 2005. PMID: 16298354