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HOGA1
4-hydroxy-2-oxoglutarate aldolase 1
The HOGA1 gene encodes the 4-hydroxy-2-oxoglutarate aldolase enzyme, which is primarily active in the liver and kidneys and plays a role in the metabolism of hydroxyproline. HOGA1 provides instructions for an enzyme crucial for breaking down 4-hydroxy-2-oxoglutarate, a substance involved in hydroxyproline metabolism.
HOGA1 is located on the long (q) arm of chromosome 10, at band 10q24.2. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
The HOGA1 gene, also known as 4-hydroxy-2-oxoglutarate aldolase 1, produces an enzyme called 4-hydroxy-2-oxoglutarate aldolase. This enzyme is predominantly found in the liver and kidney cells, specifically within the mitochondria, which are the powerhouses of the cell. Its primary role involves a specific step in the breakdown of the amino acid hydroxyproline.
What the gene does
The HOGA enzyme encoded by the HOGA1 gene is integral to the metabolic pathway of hydroxyproline. Within the mitochondria, the HOGA enzyme is responsible for cleaving a molecule called 4-hydroxy-2-oxoglutarate. This cleavage reaction yields two smaller substances: pyruvate and glyoxylate. While pyruvate is understood to participate in energy production pathways, the precise function of glyoxylate produced in this context is not yet fully elucidated. Disruptions to this enzymatic process can lead to metabolic imbalances, notably affecting oxalate levels in the body.
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Chromosome location
The HOGA1 gene is situated on chromosome 10, specifically at position 10q24.2. This genomic location refers to the long (q) arm of chromosome 10, within region 2, band 4, and sub-band 2.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The HOGA1 protein consists of 327 amino acids.
Key variants
Variants within the HOGA1 gene can impact the function of the 4-hydroxy-2-oxoglutarate aldolase enzyme. Changes in the gene's DNA sequence may lead to a non-functional or less efficient enzyme, thereby disrupting its metabolic role. Research has identified various alterations in HOGA1 that are associated with inherited 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.110G>A | p.Gly37Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria type 3 |
c.122del | p.Pro41fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria type 3 |
c.186_187del | p.His62fs | Pathogenic | ★★☆☆ | Primary hyperoxaluria type 3 |
c.290G>A | p.Arg97His | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria type 3 |
c.2T>G | p.Met1Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria type 3 |
c.388del | p.Ala130fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria type 3 |
c.3G>A | p.Met1Ile | Pathogenic | ★★☆☆ | Primary hyperoxaluria type 3 |
c.733G>T | p.Val245Phe | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria type 3 |
c.834+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria type 3 |
c.860G>A | p.Gly287Glu | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria type 3 |
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 in the HOGA1 gene are primarily associated with primary hyperoxaluria type 3, which is inherited in an autosomal recessive pattern. This condition is characterised by an overproduction of oxalate, leading to the formation of kidney and bladder stones, often beginning in early childhood. Symptoms can include blood in the urine (haematuria) and recurrent urinary tract infections.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic HOGA1 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 HOGA1 gene is included in several UK NHS national genomic testing panels. These include panels for "Likely inborn error of metabolism", "Nephrocalcinosis or nephrolithiasis", "Peroxisomal disorders", and "Undiagnosed metabolic disorders", indicating its recognised clinical significance in these areas within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the HOGA1 gene?
The HOGA1 gene provides instructions for creating the 4-hydroxy-2-oxoglutarate aldolase enzyme. This enzyme plays a role in the breakdown of hydroxyproline, specifically by cleaving 4-hydroxy-2-oxoglutarate into pyruvate and glyoxylate.
What condition is associated with HOGA1 gene variants?
Variants in the HOGA1 gene are primarily associated with primary hyperoxaluria type 3. This is an inherited metabolic disorder characterised by excessive oxalate production, which can lead to kidney and bladder stones.
Where in the body is the HOGA enzyme found?
The HOGA enzyme, produced from the HOGA1 gene, is predominantly found within the mitochondria of liver and kidney cells. Mitochondria are the cellular components responsible for energy generation.
References
- Cochat P, Rumsby G. Primary hyperoxaluria. The New England journal of medicine. 2013. PMID: 23944302
- Williams EL, Bockenhauer D, van't Hoff WG. The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2012. PMID: 22391140
- Hoppe B. The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type III. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2012. PMID: 22851625
- Riedel TJ, Johnson LC, Knight J. Structural and biochemical studies of human 4-hydroxy-2-oxoglutarate aldolase: implications for hydroxyproline metabolism in primary hyperoxaluria. PloS one. 2011. PMID: 21998747
- Adam MP, Bick S, Mirzaa GM. Primary Hyperoxaluria Type 3. 1993. PMID: 26401545