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HPD
4-hydroxyphenylpyruvate dioxygenase
The HPD gene provides instructions for an enzyme crucial in the breakdown of the amino acid tyrosine, with genetic changes linked to inherited metabolic disorders. The HPD gene codes for 4-hydroxyphenylpyruvate dioxygenase, an enzyme predominantly found in the liver that plays a key role in the metabolic pathway of tyrosine.
HPD is located on the long (q) arm of chromosome 12, at band 12q24.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The HPD gene encodes the enzyme 4-hydroxyphenylpyruvate dioxygenase, which is vital for the proper metabolism of the amino acid tyrosine. This enzyme is predominantly expressed in the liver, with smaller quantities found in the kidneys. It performs a specific step in the breakdown pathway of tyrosine, converting 4-hydroxyphenylpyruvate into homogentisic acid. Impaired function of this enzyme, due to genetic changes in the HPD gene, can lead to the accumulation of metabolic byproducts, contributing to various health conditions.
The HPD gene is categorised as an autosomal recessive gene in carrier screening, meaning individuals typically need to inherit a pathogenic variant from each parent to be affected by an associated condition.
What the gene does
The HPD gene's primary function is to direct the production of 4-hydroxyphenylpyruvate dioxygenase, an enzyme central to the catabolism of tyrosine. Tyrosine is an amino acid obtained from the diet, and its breakdown involves a series of enzymatic steps. 4-hydroxyphenylpyruvate dioxygenase acts as the second enzyme in this specific pathway, facilitating the conversion of 4-hydroxyphenylpyruvate-a derivative of tyrosine-into homogentisic acid. This conversion is a critical step, enabling further processing of homogentisic acid into smaller molecules.
These smaller molecules are subsequently either excreted from the body via the kidneys or utilised for energy production or the synthesis of other necessary substances. When the 4-hydroxyphenylpyruvate dioxygenase enzyme activity is reduced or absent due to HPD gene variants, the breakdown pathway is disrupted, leading to a build-up of upstream metabolites which can be detrimental.
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Chromosome location
The HPD gene is located on chromosome 12 at position 12q24.31. This specific genomic location indicates its precise address within the human genome. The gene provides the genetic blueprint for a protein that is 393 amino acids long.
Protein structure
The 4-hydroxyphenylpyruvate dioxygenase protein comprises 393 amino acids. Its structure includes distinct functional regions, such as the VOC 1 domain spanning amino acids 18-149 and the VOC 2 domain located between amino acids 180-338. These domains are integral to the enzyme's catalytic activity and its interaction with substrates during the tyrosine breakdown pathway.
Key variants
Variants within the HPD gene can alter the function of the 4-hydroxyphenylpyruvate dioxygenase enzyme, impacting its ability to metabolise tyrosine effectively. These genetic changes can range from single amino acid substitutions to larger alterations, potentially leading to reduced enzyme activity or complete loss of function. The specific variant and its effect on enzyme activity can influence the clinical presentation and severity of associated conditions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.613C>T | p.Gln205Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinemia type III |
c.673C>T | p.Arg225Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hawkinsinuria |
g.(?_122277432)_(122296766_?)del | - | Pathogenic | ★☆☆☆ | Tyrosinemia type III |
g.(?_122277634)_(122287716_?)del | - | Pathogenic | ★☆☆☆ | Tyrosinemia type III |
g.(?_122284839)_(122288809_?)del | - | Pathogenic | ★☆☆☆ | Tyrosinemia type III |
g.(?_122286885)_(122287716_?)del | - | Pathogenic | ★☆☆☆ | Tyrosinemia type III |
g.(?_122292589)_(122296729_?)del | - | Pathogenic | ★☆☆☆ | Tyrosinemia type III |
g.(?_122294469)_(122296729_?)del | - | Pathogenic | ★☆☆☆ | Tyrosinemia type III |
c.442dup | p.Glu148fs | Pathogenic | ★☆☆☆ | Tyrosinemia type III |
c.535del | p.Glu179fs | Pathogenic | ★☆☆☆ | Tyrosinemia type III |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the HPD gene are primarily associated with inherited metabolic disorders affecting tyrosine metabolism. One such condition is Tyrosinaemia type III, which is characterised by neurological symptoms like intellectual disability, seizures, and episodes of ataxia. Additionally, certain HPD gene variants have been identified in individuals with hawkinsinuria, a rare condition in infants presenting with faltering weight and acidosis. Both conditions arise from deficient 4-hydroxyphenylpyruvate dioxygenase activity.
- Tyrosinaemia type III Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic HPD 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 HPD gene is recognised within several UK NHS Genomic Medicine Service (GMS) approved panels, signifying its clinical importance in the UK. It is included in the DDG2P panel, as well as panels for Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders, all of which are designated green, indicating that there is strong evidence for the gene's association with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of the HPD gene?
The HPD gene contains instructions for making the enzyme 4-hydroxyphenylpyruvate dioxygenase. This enzyme is crucial for breaking down the amino acid tyrosine, converting one of its byproducts into another compound further down the metabolic pathway.
What happens if the HPD gene doesn't work correctly?
If the HPD gene has pathogenic variants, the enzyme it produces may not function properly. This can lead to an accumulation of tyrosine breakdown products in the body, which is associated with conditions like Tyrosinaemia type III and hawkinsinuria, affecting neurological function and overall metabolism.
Is Tyrosinaemia type III an inherited condition?
Yes, Tyrosinaemia type III is an inherited condition typically passed down in an autosomal recessive pattern. This means an individual must inherit a pathogenic variant in the HPD gene from both parents to develop the condition.
References
- Heylen E, Scherer G, Vincent MF. Tyrosinemia Type III detected via neonatal screening: management and outcome. Molecular genetics and metabolism. 2012. PMID: 23036342
- Brownlee JM, Heinz B, Bates J. Product analysis and inhibition studies of a causative Asn to Ser variant of 4-hydroxyphenylpyruvate dioxygenase suggest a simple route to the treatment of Hawkinsinuria. Biochemistry. 2010. PMID: 20677779
- Aarenstrup L, Falch AM, Jakobsen KK. Expression and post-translational modification of human 4-hydroxy-phenylpyruvate dioxygenase. Cell biology international. 2002. PMID: 12127941
- Ellaway CJ, Holme E, Standing S. Outcome of tyrosinaemia type III. Journal of inherited metabolic disease. 2001. PMID: 11916315
- Rüetschi U, Cerone R, Pérez-Cerda C. Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III. Human genetics. 2000. PMID: 10942115
- Tomoeda K, Awata H, Matsuura T. Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria. Molecular genetics and metabolism. 2000. PMID: 11073718