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HGD
homogentisate 1,2-dioxygenase
The HGD gene provides instructions for the homogentisate 1,2-dioxygenase enzyme, which plays a crucial role in the breakdown of specific amino acids. The HGD gene encodes an enzyme primarily active in the liver and kidneys, involved in metabolising phenylalanine and tyrosine.
HGD is located on the long (q) arm of chromosome 3, at band 3q13.33. Arm ratio per GRCh38 - banding schematic.
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Overview
The HGD gene, or homogentisate 1,2-dioxygenase, is vital for a specific step in the metabolic pathway that breaks down the amino acids phenylalanine and tyrosine. This enzyme is mainly active in the liver and kidneys, where it helps process these protein building blocks when they are no longer needed or are present in excess. These amino acids are also involved in forming brain chemicals, hormones, and pigments.
What the gene does
The HGD gene provides instructions for creating the homogentisate 1,2-dioxygenase enzyme. This enzyme participates in a multi-step process that dismantles phenylalanine and tyrosine. Earlier stages convert these amino acids into a molecule called homogentisic acid. The homogentisate 1,2-dioxygenase enzyme then adds two oxygen atoms to homogentisic acid, transforming it into maleylacetoacetate. Further enzymatic reactions break down maleylacetoacetate into smaller molecules, which the body can then use for energy production or to synthesise other essential compounds.
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Chromosome location
The HGD gene is located on chromosome 3, specifically at position 3q13.33. This genomic location specifies its precise address within the human genome.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the HGD gene can alter the function of the homogentisate 1,2-dioxygenase enzyme. Hundreds of different changes have been identified, primarily affecting single amino acids within the enzyme. These genetic alterations can significantly reduce the enzyme's activity, leading to metabolic disruptions.
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.105C>A | p.Cys35Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Alkaptonuria |
c.1079G>T | p.Gly360Val | Pathogenic/Likely pathogenic | ★★☆☆ | Alkaptonuria |
c.504G>C | p.Glu168Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Alkaptonuria |
c.549+1G>T | - | Pathogenic | ★★☆☆ | Alkaptonuria |
c.1021G>T | p.Glu341Ter | Pathogenic | ★☆☆☆ | Alkaptonuria |
c.113del | p.Asn38fs | Pathogenic | ★☆☆☆ | Alkaptonuria |
c.146del | p.Phe49fs | Pathogenic | ★☆☆☆ | Alkaptonuria |
c.2T>C | p.Met1Thr | Pathogenic | ★☆☆☆ | Alkaptonuria |
c.781del | p.Ser261fs | Pathogenic | ★☆☆☆ | Alkaptonuria |
c.803G>A | p.Trp268Ter | Pathogenic | ★☆☆☆ | Alkaptonuria |
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
Pathogenic variants within the HGD gene are known to cause Alkaptonuria. This inherited metabolic condition is characterised by various symptoms, including arthritis, the formation of kidney stones, and distinct areas of dark pigmentation in body tissues, as well as dark urine. The reduction in enzyme function due to HGD variants underlies the development of these symptoms.
UK clinical status
In the UK, the HGD gene is included in NHS England's PanelApp, listed under the 'Likely inborn error of metabolism' (green, R98) and 'Undiagnosed metabolic disorders' panels. This inclusion signifies its recognised role in inherited metabolic conditions within a clinical diagnostic context.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the HGD gene?
The HGD gene provides instructions for the homogentisate 1,2-dioxygenase enzyme, which is crucial for breaking down the amino acids phenylalanine and tyrosine in the liver and kidneys.
What condition is associated with HGD gene variants?
Pathogenic variants in the HGD gene are known to cause Alkaptonuria, a metabolic disorder characterised by arthritis, kidney stones, and dark pigmentation.
Where is the HGD gene located?
The HGD gene is found on chromosome 3, specifically at the position 3q13.33.
References
- Amaya AA, Brzezinski KT, Farrington N. Kinetic analysis of human homogentisate 1,2-dioxygenase. Archives of biochemistry and biophysics. 2004. PMID: 14678794
- Zatkova A, Chmelikova A, Polakova H. Rapid detection methods for five HGO gene mutations causing alkaptonuria. Clinical genetics. 2003. PMID: 12630963
- Srsen S, Müller CR, Fregin A. Alkaptonuria in Slovakia: thirty-two years of research on phenotype and genotype. Molecular genetics and metabolism. 2002. PMID: 12051967
- Goicoechea De Jorge E, Lorda I, Gallardo ME. Alkaptonuria in the Dominican Republic: identification of the founder AKU mutation and further evidence of mutation hot spots in the HGO gene. Journal of medical genetics. 2002. PMID: 12114497
- Rodríguez JM, Timm DE, Titus GP. Structural and functional analysis of mutations in alkaptonuria. Human molecular genetics. 2000. PMID: 11001939
- Adam MP, Bick S, Mirzaa GM. Alkaptonuria. 1993. PMID: 20301627