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GRHPR
glyoxylate and hydroxypyruvate reductase
The GRHPR gene encodes an enzyme, glyoxylate and hydroxypyruvate reductase, that plays a key role in metabolic pathways, primarily by converting potentially harmful substances into forms that can be easily eliminated from the body. The GRHPR gene is essential for proper metabolism, specifically in the processing of glyoxylate and hydroxypyruvate.
GRHPR is located on the short (p) arm of chromosome 9, at band 9p13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The GRHPR gene provides instructions for making the enzyme glyoxylate and hydroxypyruvate reductase. This enzyme is vital for metabolic processes that prevent the accumulation of glyoxylate, a potentially harmful substance, by converting it into glycolate, which the body can easily excrete. The enzyme also converts hydroxypyruvate into D-glycerate, which can then be used in glucose production.
Disruptions in the GRHPR gene's function can lead to metabolic imbalances, most notably primary hyperoxaluria type 2. This condition is characterised by the excessive production and accumulation of oxalate, a by-product of glyoxylate metabolism, which can lead to kidney stones and kidney disease.
What the gene does
The GRHPR gene product, glyoxylate and hydroxypyruvate reductase, functions as a critical enzyme in multiple metabolic pathways. Its primary role involves the detoxification of glyoxylate, a compound that can become toxic if it builds up in the body. The enzyme achieves this by catalysing the conversion of glyoxylate to glycolate, a less harmful substance that is readily excreted through the urine.
In addition to glyoxylate metabolism, the GRHPR enzyme also participates in the metabolism of hydroxypyruvate. It converts hydroxypyruvate into D-glycerate, which is subsequently converted into glucose by other enzymes, providing a source of energy for the body. Therefore, the GRHPR enzyme is crucial for maintaining metabolic balance and preventing the accumulation of toxic by-products within cells.
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Chromosome location
The GRHPR gene is found on chromosome 9, specifically at the location 9p13.2. This indicates its position on the short (p) arm of chromosome 9, within region 1, band 3, sub-band 2.
Protein structure
The GRHPR protein is composed of 328 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the GRHPR gene can alter the function of the glyoxylate and hydroxypyruvate reductase enzyme. Over 25 different pathogenic variants have been identified in the GRHPR gene that are associated with inherited conditions. These changes can reduce the enzyme's efficiency in processing its substrates, leading to metabolic imbalances and the accumulation of harmful substances.
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.102_112del | p.Trp34_Glu38delinsTer | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type II |
c.259del | p.His87fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type II |
c.271del | p.Asp91fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type II |
c.287_287+4delinsCCC | - | Pathogenic | ★★☆☆ | Primary hyperoxaluria, type II |
c.412T>C | p.Trp138Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type II |
c.494-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type II |
c.516_532dup | p.Gln178fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type II |
c.622C>T | p.Gln208Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type II |
c.626C>T | p.Ser209Phe | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type II |
c.865+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Primary hyperoxaluria, type II |
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 GRHPR gene are linked to primary hyperoxaluria type 2. This is an inherited metabolic disorder characterised by the overproduction of oxalate, a waste product. The accumulation of excess oxalate leads to the formation of kidney and bladder stones, often beginning in childhood, and can progress to kidney disease. Oxalate can also deposit in other tissues throughout the body, a condition known as systemic oxalosis.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic GRHPR 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 GRHPR gene is included in several NHS England Genomic Medicine Service national test panels. It is listed with a 'green' status on the 'Likely inborn error of metabolism', 'Nephrocalcinosis or nephrolithiasis', 'Peroxisomal disorders', and 'Undiagnosed metabolic disorders' panels, indicating strong evidence for its association with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the GRHPR gene do?
The GRHPR gene provides instructions for an enzyme called glyoxylate and hydroxypyruvate reductase. This enzyme helps the body process certain substances, preventing the build-up of potentially harmful compounds like glyoxylate, which it converts into glycolate for excretion.
What condition is associated with GRHPR gene variants?
Pathogenic variants in the GRHPR gene are associated with primary hyperoxaluria type 2. This condition leads to the overproduction of oxalate, which can cause kidney and bladder stones and may result in kidney disease.
How is primary hyperoxaluria type 2 inherited?
Primary hyperoxaluria type 2 is inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the GRHPR gene, one from each parent, to develop the condition. Individuals with only one altered copy are typically carriers and do not show symptoms.
References
- Cochat P, Rumsby G. Primary hyperoxaluria. The New England journal of medicine. 2013. PMID: 23944302
- Hoppe B. An update on primary hyperoxaluria. Nature reviews. Nephrology. 2012. PMID: 22688746
- Knight J, Holmes RP. Mitochondrial hydroxyproline metabolism: implications for primary hyperoxaluria. American journal of nephrology. 2005. PMID: 15849464
- Cregeen DP, Williams EL, Hulton S. Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2. Human mutation. 2003. PMID: 14635115
- Webster KE, Ferree PM, Holmes RP. Identification of missense, nonsense, and deletion mutations in the GRHPR gene in patients with primary hyperoxaluria type II (PH2). Human genetics. 2000. PMID: 11030416
- Adam MP, Bick S, Mirzaa GM. Primary Hyperoxaluria Type 2. 1993. PMID: 20301742