Primary hyperoxaluria - AGXT, GRHPR and HOGA1 genes 

Primary hyperoxaluria is a rare disease characterized by excess production of oxalate (oxalic acid). This condition often results in end-stage renal disease (ESRD). In the kidneys, excess oxalate combines with calcium to form calcium oxalate, the main component of kidney stones. Calcium oxalate deposits can lead to kidney damage, kidney failure and injury to other organs. As the oxalate concentrations in the blood rise, it causes a systemic oxalosis, especially in the bones and walls of the blood vessels. Oxalosis in bones can cause fractures.

There are three types of primary hyperoxaluria that differ in their severity and genetic cause. In primary type 1 hyperoxaluria, kidney stones usually begin to appear at any time between childhood and early adulthood, and end-stage renal disease (ESRD) can develop at any age. Primary hyperoxaluria type 2 is similar to type 1, but ESRD develops later in life. In primary type 3 hyperoxaluria, affected individuals often develop kidney stones early in childhood, however, because few cases of this type are described, the additional signs and symptoms are not clear.

Mutations in the AGXT (alanine-glyoxylate aminotransferase), GRHPR (glyoxylate reductase / hydroxypyruvate reductase) and HOGA1 (4-hydroxy-2-oxoglutarate aldolase 1) genes are responsible for primary hyperoxaluria types 1, 2, and 3, respectively. These genes encode enzymes that are involved in the degradation and processing of amino acids and other compounds.

The AGXT (alanine-glyoxylate aminotransferase) gene, located on the long arm of chromosome 2 (2q37.3), encodes the enzyme alanine aminotransferase-glyoxylate. This enzyme is found in the peroxisomes of liver cells. These structures are important for several cellular activities, such as freeing the cell of toxic substances and helping to break down certain fats. In the peroxisome, the alanine aminotransferase-glyoxylate converts a compound called glyoxylate into the amino acid glycine. So far, more than 175 mutations in the AGXT gene have been identified in people with primary type 1 hyperoxaluria. Most of these mutations decrease or eliminate the activity of alanine aminotransferase-glyoxylate, which alters the conversion of glyoxylate to glycine. Other mutations result in the synthesis of an enzyme found in mitochondria instead of in peroxisomes. Although the enzyme in the mitochondria retains the activity, it cannot access glyoxylate, which is found in peroxisomes. As a result, there is an accumulation of glyoxylate that is converted to oxalate instead of glycine. Oxalate is filtered by the kidneys and excreted in the urine, either as a waste product or combined with calcium to form calcium oxalate. Increased concentrations of oxalate in the blood can lead to systemic oxalosis.

The GRHPR (glyoxylate reductase / hydroxypyruvate reductase) gene, located on the long arm of chromosome 9 (9q12), encodes the enzyme glyoxylate reductase / hydroxypyruvate reductase. This enzyme plays a role in preventing the accumulation of glyoxylate by converting it to glycolate, which is easily excreted from the body. In addition, this enzyme can convert a compound called hydroxypyruvate to D-glycerate, which is eventually converted to glucose and used for energy. More than 25 mutations in the GRHPR gene have been described in people with primary hyperoxaluria type 2. These genetic changes inhibit the synthesis of reductase glyoxylate reductase / hydroxypyruvate or alter its structure. As a result, the conversion of glyoxylate to glycolate is impaired, which causes the glyoxylate to accumulate and become oxalate.

The HOGA1 (4-hydroxy-2-oxoglutarate aldolase 1) gene, located on the long arm of chromosome 10 (10q24.2), encodes the enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA). This enzyme is found in the cells of the liver and kidneys, specifically inside the mitochondria. The enzyme HOGA participates in the degradation of the amino acid hydroxyproline. Specifically, during the grading process, HOGA cleaves a substance called 4-hydroxy-2-oxoglutarate to produce two smaller substances: pyruvate and glyoxylate. In mitochondria, pyruvate is likely to participate in the production of energy, but the function of glyoxylate is not clear. At least 24 mutations in the HOGA1 gene have been identified in people with primary type 3 hyperoxaluria. A specific mutation that alters the encoding of the enzyme (700 + 5G> T) is present in approximately half of the affected individuals. As consequence of the HOGA1 gene mutations, the HOGA enzyme cannot decompose 4-hydroxy-2-oxoglutarate, which causes an accumulation of this substance in the mitochondria of the liver cells. It is not clear how an accumulation of 4-hydroxy-2-oxoglutarate leads to an overproduction of oxalate in people with primary type hyperoxaluria 3. It is believed that the accumulation of 4-hydroxy-2-oxoglutarate interferes with the activity of other enzymes, which result in the accumulation of substances that are converted to oxalate. Other authors indicate that excess 4-hydroxy-2-oxoglutarate in mitochondria can leak into the interior of liver cells. Enzymes inside these cells would subsequently convert 4-hydroxy-2-oxoglutarate to glyoxylate, and glyoxylate into oxalate.

This disease is inherited with an autosomal recessive pattern, that is, both copies of the gene in each cell must have the mutations so that the alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Primary hyperoxaluria, by means of the complete PCR amplification of the exons of the AGXT, GRHPR y HOGA1 genes, respectively, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).