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AGXT
alanine--glyoxylate aminotransferase
The AGXT gene provides instructions for making an enzyme in the liver that converts glyoxylate to glycine, preventing the accumulation of harmful oxalate. Located on chromosome 2, AGXT encodes alanine-glyoxylate aminotransferase, a peroxisomal enzyme essential for glyoxylate metabolism in the liver.
AGXT is located on the long (q) arm of chromosome 2, at band 2q37.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The AGXT gene encodes alanine-glyoxylate aminotransferase, a specialised enzyme that operates within peroxisomes in liver cells. Peroxisomes are small compartments within cells responsible for breaking down toxic substances and processing certain fats. The enzyme produced by AGXT plays a critical role in preventing the buildup of glyoxylate, a potentially harmful compound, by converting it into glycine, an amino acid the body can safely use.
When AGXT functions normally, it maintains appropriate levels of glyoxylate and prevents the formation of oxalate, a substance that can crystallise and cause damage throughout the body. Pathogenic variants in this gene disrupt this metabolic pathway, leading to excess oxalate production. This metabolic imbalance is the underlying cause of primary hyperoxaluria type 1, a rare inherited condition that typically manifests with kidney and bladder stones.
What the gene does
Alanine-glyoxylate aminotransferase catalyses the conversion of glyoxylate to glycine within the peroxisome, a reaction that requires the vitamin B6 derivative pyridoxal phosphate as a cofactor. This enzymatic activity represents a crucial step in glyoxylate detoxification, as glyoxylate can otherwise be converted to oxalate, a compound with limited solubility that readily forms crystals.
The enzyme's localisation to peroxisomes is essential for its function, as these organelles are the primary site of glyoxylate production from glycolate metabolism. By efficiently converting glyoxylate to glycine at the site of its generation, the enzyme prevents glyoxylate from entering other metabolic pathways that would produce oxalate. The protein also exhibits serine-pyruvate aminotransferase activity, contributing to amino acid metabolism more broadly.
Proper functioning of this enzyme depends not only on its catalytic activity but also on correct trafficking to the peroxisome. Some pathogenic variants affect the enzyme's ability to reach its intended location within the cell, while others reduce its catalytic efficiency or stability once properly localised.
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Chromosome location
The AGXT gene is located on the long arm of chromosome 2 at position 37.3 (2q37.3). This chromosomal region lies near the telomere, or end, of chromosome 2. The gene spans multiple exons that encode the 392-amino-acid protein.
Protein structure
The alanine-glyoxylate aminotransferase protein consists of 392 amino acids that fold to create the active enzyme. As a member of the aminotransferase family, the protein contains regions responsible for binding pyridoxal phosphate, the essential vitamin B6-derived cofactor required for its enzymatic activity. The protein also contains a peroxisomal targeting sequence that directs it to the correct cellular compartment, ensuring it can access glyoxylate molecules where they are produced.
Key variants
More than 175 pathogenic variants in the AGXT gene have been identified, most of which cause primary hyperoxaluria type 1. These variants include missense changes that alter single amino acids, as well as deletions, insertions, and variants affecting RNA splicing. Some variants reduce the enzyme's catalytic activity, while others prevent the protein from reaching the peroxisome or cause it to misfold and degrade prematurely. The severity of oxalate overproduction can vary depending on the specific variant and how much residual enzyme activity remains.
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.139G>C | p.Gly47Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type I |
c.244G>A | p.Gly82Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria |
c.252_253del | p.Ala85fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type I |
c.358+1G>A | - | Pathogenic | ★★☆☆ | Primary hyperoxaluria, type I |
c.433del | p.Gln145fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type I |
c.508G>C | p.Gly170Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria |
c.595+1G>T | - | Pathogenic | ★★☆☆ | Primary hyperoxaluria, type I |
c.622C>T | p.Gln208Ter | Pathogenic | ★★☆☆ | Primary hyperoxaluria |
c.733_734del | p.Lys245fs | Pathogenic | ★★☆☆ | Primary hyperoxaluria, type I |
c.807dup | p.Tyr270fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type I |
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 AGXT cause primary hyperoxaluria type 1, a rare metabolic disorder characterised by excessive production and accumulation of oxalate. This condition typically presents with recurrent kidney stones and nephrocalcinosis (calcium deposits in the kidneys), which can begin in childhood or early adulthood. The excess oxalate can also deposit in other tissues throughout the body, including bones, eyes, heart, and blood vessels, particularly when kidney function declines.
The age of onset and severity of primary hyperoxaluria type 1 vary considerably between individuals. Some people develop kidney stones in early childhood, while others remain asymptomatic until adulthood. Progressive kidney damage may occur, and in severe cases, kidney failure develops. The condition follows an autosomal recessive inheritance pattern, meaning affected individuals typically inherit one pathogenic variant from each parent.
No disease links recorded for this gene in our reference set.
UK clinical status
The AGXT gene appears on several NHS Genomic Medicine Service panels with green classification, indicating strong evidence for its role in human disease. These include the DDG2P panel, the Likely Inborn Error of Metabolism panel (R98), the Nephrocalcinosis or Nephrolithiasis panel (R256), the Peroxisomal Disorders panel, the Undiagnosed Metabolic Disorders panel, and the Hereditary Neuropathy or Pain Disorder panel (R78). This broad panel representation reflects the gene's established role in metabolic disease and the diverse clinical presentations that can result from AGXT variants.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for AGXT-related conditions?
Primary hyperoxaluria type 1 follows an autosomal recessive inheritance pattern. This means an individual must inherit pathogenic variants in both copies of the AGXT gene (one from each parent) to develop the condition. Parents who each carry one pathogenic variant typically do not show symptoms but have a 25% chance with each pregnancy of having an affected child.
How does vitamin B6 relate to AGXT function?
The alanine-glyoxylate aminotransferase enzyme requires pyridoxal phosphate, a form of vitamin B6, to function as a cofactor. Some individuals with certain AGXT variants respond to high-dose vitamin B6 supplementation with reduced oxalate production, though this response is variant-specific and not universal. Individuals should discuss any supplementation with their healthcare provider before starting treatment.
Can AGXT variants affect organs other than the kidneys?
Yes, when oxalate levels become very high, particularly if kidney function declines, oxalate crystals can deposit in multiple tissues throughout the body. This systemic oxalosis can affect bones, eyes, heart, blood vessels, and other organs, leading to a range of complications beyond kidney stones.
References
- Hopp K, Cogal AG, Bergstralh EJ. Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. Journal of the American Society of Nephrology : JASN. 2015. PMID: 25644115
- Cochat P, Rumsby G. Primary hyperoxaluria. The New England journal of medicine. 2013. PMID: 23944302
- Williams EL, Acquaviva C, Amoroso A. Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. Human mutation. 2009. PMID: 19479957
- Adam MP, Bick S, Mirzaa GM. Primary Hyperoxaluria Type 1. 1993. PMID: 20301460