AGXT

The AGXT gene encodes the enzyme alanine-glyoxylate aminotransferase (AGT), primarily located in the liver's peroxisomes and crucial for converting glyoxylate into glycine, thereby detoxifying glyoxylate. 

Mutations in this gene can lead to mistargeting of the enzyme to mitochondria, significantly impacting its function and resulting in Primary Hyperoxaluria Type I, characterized by excessive kidney and urinary tract calcium oxalate deposits. 

Understanding AGXT: What is the AGXT Enzyme and Gene?  [1., 2., 3.]

Alanine-glyoxylate aminotransferase (AGXT) is a liver enzyme that converts glyoxylate into glycine, a critical reaction in the glyoxylate detoxification pathway.

The AGXT gene, expressed exclusively in the liver, encodes the enzyme alanine:glyoxylate aminotransferase (AGT), which is primarily found in peroxisomes and plays a critical role in glyoxylate detoxification. 

Mutations in this gene can disrupt the enzyme’s usual peroxisomal localization, leading to mistargeting to mitochondria, a phenomenon associated with type I primary hyperoxaluria.  This condition, characterized by excessive calcium oxalate deposits in the kidneys, is typically caused by deficient or mistargeted AGT activity due to various mutations within the AGXT gene.

Alterations in the AGXT Gene and Primary Hyperoxaluria  [4.]

AGXT catalyzes the conversion of glyoxylate into glycine, a critical reaction in the glyoxylate detoxification pathway.  This enzymatic activity is essential for preventing the accumulation of glyoxylate, which can otherwise be converted into oxalate. 

Oxalate is a compound that, when excessively accumulated, can lead to the formation of kidney stones and other renal complications.  The enzyme's ability to regulate glyoxylate levels directly impacts the body’s overall metabolic balance and highlights its role in maintaining renal health.

The gene for the AGXT protein may contain alterations or mutations that cause increase or decrease of function of the AGXT protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

The AGXT gene is pivotal in the development of Primary Hyperoxaluria type 1 (PH1), the most severe form of Primary Hyperoxaluria. 

This condition results from a deficiency of the enzyme alanine-glyoxylate aminotransferase, leading to the excessive production of oxalate which accumulates in the kidneys and other organs, causing recurrent kidney stones and renal failure. 

Various mutations in AGXT including mistargeting alleles like p.G170R, influence the severity and treatment responsiveness of the disease, highlighting the critical role of genetic testing in managing these patients effectively.

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

SNPs Associated with Alterations in AGXT Function  [2.]

pG170R:  [4.]

The AGXT p.G170R mutation results in the mistargeting of the alanine-glyoxylate aminotransferase enzyme to mitochondria rather than peroxisomes, leading to a milder form of Primary Hyperoxaluria type 1. 

Patients with this mutation typically experience less severe renal disease and may respond positively to pyridoxine treatment, which helps reduce enzyme mistargeting.

p.Gly27Glu: 

This novel missense mutation replaces a buried uncharged residue (Glycine) with a charged residue (Glutamic acid), potentially destabilizing the protein structure and leading to dysfunction in enzyme activity.

p.Gln256Serfs*17: 

This novel frameshift mutation results in a premature stop codon, likely producing a truncated protein that could disrupt the normal function of the enzyme and lead to severe clinical manifestations.

p.Lys12Glnfs*156: 

A frameshift mutation leading to a premature termination codon, resulting in a truncated protein that significantly impairs the enzyme's functionality and is commonly observed in patients with severe manifestations.

p.Lys12Argfs*34: 

Another frameshift mutation that introduces a premature stop codon, resulting in a truncated protein that severely affects enzyme function and is associated with early onset and severe symptoms of the disease.

p.Ile244Thr: 

This missense mutation changes an isoleucine to a threonine, potentially affecting the protein's stability and function, contributing to the disease phenotype.

p.Asn22Ser: 

This missense mutation substitutes an asparagine with a serine, which might affect the enzyme's activity and stability, impacting glyoxylate metabolism.

p.Pro11Leu: 

This missense mutation changes a proline to a leucine at a crucial site for protein function, reducing catalytic activity and contributing to the mistargeting of the enzyme from peroxisomes to mitochondria.

p.Ile340Met: 

A missense mutation altering isoleucine to methionine, potentially decreasing the enzyme's expression and activity, which affects the regulation of glyoxylate and oxalate concentrations in the body.

Laboratory Testing for AGXT

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing.  Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

Biomarkers Related to AGXT

Glycolate and Oxalate: Their Roles in Metabolism and How They Are Tested

Glycolate and oxalate are closely linked to AGXT activity and play critical roles in metabolic pathways that affect kidney health. Glycolate, a precursor to glyoxylate, can provide insights into the upstream metabolic activity, while oxalate, the downstream product of glyoxylate metabolism when AGXT is deficient, is directly involved in the formation of kidney stones and renal complications. 

Laboratory testing for these compounds typically involves urine and plasma analysis using techniques like gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). 

Measuring levels of these metabolites can help in confirming the diagnosis of conditions like Primary Hyperoxaluria and monitoring the effectiveness of dietary and pharmacological interventions aimed at reducing their production.

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