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GRHPR
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GRHPR

The GRHPR gene encodes glyoxylate reductase/hydroxypyruvate reductase, a dual-function enzyme essential for detoxifying glyoxylate and supporting glucose metabolism. 

Mutations in GRHPR disrupt these pathways, leading to Primary Hyperoxaluria Type 2 (PH2), a rare autosomal recessive disorder marked by recurrent kidney stones, nephrocalcinosis, and progressive renal damage.

What is GRHPR (Glyoxylate Reductase/Hydroxypyruvate Reductase)?

GRHPR is a gene located on chromosome 9p13.2 that provides instructions for making a dual-function enzyme called glyoxylate reductase/hydroxypyruvate reductase (GRHPR). This enzyme detoxifies glyoxylate and maintains normal energy metabolism.

GRHPR: A Dual-Function Enzyme in Glyoxylate Metabolism

The GRHPR enzyme catalyzes two important reactions:

Converts glyoxylate to glycolate – this prevents glyoxylate from being turned into oxalate, which can form kidney stones.

Converts hydroxypyruvate to D-glycerate – a step that feeds into glucose production for energy.

A deficiency in GRHPR disrupts these reactions, allowing glyoxylate to accumulate and convert into oxalate, leading to a rare condition called Primary Hyperoxaluria Type 2 (PH2).

GRHPR has also been associated with certain cancers in research, specifically non-small cell lung cancer (NSCLC). 

Primary Hyperoxaluria Type 2 (PH2): GRHPR-Related Disorder

Primary hyperoxaluria type 2, also called glyoxylate reductase/hydroxypyruvate reductase deficiency, is a rare inherited condition caused by mutations in both copies of the GRHPR gene. 

This gene makes the GRHPR enzyme, which helps break down glyoxylate and hydroxypyruvate in the liver. When this enzyme doesn't work correctly, glyoxylate builds up and is converted into oxalate, leading to high oxalate levels in the urine.

Too much oxalate causes calcium oxalate kidney stones (nephrolithiasis), calcium deposits in the kidney tissue (nephrocalcinosis), and can lead to end-stage kidney disease (ESKD). Once kidney function declines, oxalate builds up throughout the body (oxalosis), affecting bones, joints, eyes, heart, and other organs.

PH2 usually starts in childhood but may not be diagnosed until later. Genetic testing confirms the condition by finding disease-causing mutations in the GRHPR gene. Low enzyme activity in a liver biopsy can support the diagnosis if testing is unclear.

Treatment focuses on reducing calcium oxalate buildup. This includes high fluid intake, medications that prevent crystal formation (like potassium citrate and phosphate), and dialysis in advanced stages. In some cases, a kidney or combined liver-kidney transplant may be considered. 

PH2 is inherited in an autosomal recessive pattern, so family members may benefit from genetic counseling and testing.

GRHPR and Non-Small Cell Lung Cancer 

In non-small cell lung cancer (NSCLC), a circular RNA made from the GRHPR gene—called circ_GRHPR—is found at higher levels and helps cancer cells grow and spread by interacting with a protein called PCBP2 and increasing the activity of another cancer-related protein, FHL3.

When is GRHPR Genetic or Enzyme Testing Relevant?

Testing is recommended in the following situations:

Clinical Signs of PH2

Patients with signs and symptoms of PH2 may benefit from GRHPR testing:

  • Recurrent kidney stones (nephrolithiasis)
  • Calcium deposits in the kidneys (nephrocalcinosis)
  • Early-onset chronic kidney disease
  • Systemic oxalosis in advanced cases (oxalate buildup in bones, vessels, and other tissues)

Elevated Urinary Oxalate

  • Persistent hyperoxaluria without a known cause
  • Elevated urinary L-glycerate may also suggest PH2

Family History of PH

Genetic testing helps identify carriers and at-risk family members.

Ruling Out Other Causes

Distinguishes PH2 from PH1 (AGXT gene), PH3 (HOGA1 gene), and secondary hyperoxaluria (from diet, bowel disorders, etc.).

Enzyme Activity Testing

Although genetic testing is more commonly used, GRHPR enzyme activity can be measured in specific cell or tissue types.

Genetic counseling is recommended to explain inheritance, family planning, and management options.

GRHPR Genetic Testing: Test Procedure and Interpretation

GRHPR is often tested as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for GRHPR genetic testing are considered to be without mutations that can alter the activity of the GRHPR proteins.

What Do Specific GRHPR Mutations Mean?

Biallelic (both copies) pathogenic mutations confirm a diagnosis of PH2.

PH2 follows an autosomal recessive pattern—both parents must be carriers for a child to be affected.

Severity can vary based on the specific mutations, such as:

  • c.103delG (frameshift) – common in Northern Europe
  • R99X (nonsense) – causes a premature stop in protein
  • c.494G>A (missense) – linked to pediatric kidney stones in India; reduces enzyme activity

What Does the Absence of Pathogenic GRHPR Mutations Mean?

Does not rule out all causes of kidney stones or hyperoxaluria.

Consider testing for:

  • PH1 (AGXT gene)
  • PH3 (HOGA1 gene)
  • Secondary hyperoxaluria (dietary, intestinal, or systemic causes)

If suspicion remains high, further genetic or metabolic testing may be necessary.

Key Clinical Takeaways

GRHPR plays a vital role in preventing oxalate overproduction.

Mutations cause Primary Hyperoxaluria Type 2, a potentially progressive kidney disease.

Early genetic diagnosis is essential for management, family screening, and potential transplant planning.

Include GRHPR in gene panels for pediatric kidney stones, especially in high-risk populations.

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See References

Chatterjee A, Sarkar K, Bank S, Ghosh S, Kumar Pal D, Saraf S, Wakle D, Roy B, Chakraborty S, Bankura B, Chattopadhyay D, Das M. Homozygous GRHPR C.494G>A mutation is deleterious that causes early onset of nephrolithiasis in West Bengal, India. Front Mol Biosci. 2022 Dec 22;9:1049620. doi: 10.3389/fmolb.2022.1049620. PMID: 36619171; PMCID: PMC9815608.

Entry - *604296 - GLYOXYLATE REDUCTASE/HYDROXYPYRUVATE REDUCTASE; GRHPR - OMIM. (2015). Omim.org. https://omim.org/entry/604296

Gene Database. (2025). GRHPR Gene - GeneCards | GRHPR Protein | GRHPR Antibody. Genecards.org. https://www.genecards.org/cgi-bin/carddisp.pl?gene=GRHPR

GRHPR glyoxylate and hydroxypyruvate reductase [Homo sapiens (human)] - Gene - NCBI. (2025). Nih.gov. https://www.ncbi.nlm.nih.gov/gene/9380

GRHPR gene: MedlinePlus Genetics. (2017). Medlineplus.gov. https://medlineplus.gov/genetics/gene/grhpr/

Hou Y, Lin J, Wang D, Zhang Y, Liang Q, Chen N, Wu J, Wu W, Liu X, Ni P. The circular RNA circ_GRHPR promotes NSCLC cell proliferation and invasion via interactions with the RNA-binding protein PCBP2. Clin Exp Pharmacol Physiol. 2021 Aug;48(8):1171-1181. doi: 10.1111/1440-1681.13523. Epub 2021 May 29. PMID: 33987874; PMCID: PMC8362189.

Rumsby G, Hulton SA. Primary Hyperoxaluria Type 2. 2008 Dec 2 [Updated 2017 Dec 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2692/

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