AGXT

The AGXT gene provides instructions for making a liver enzyme called alanine-glyoxylate aminotransferase. Inside liver cells, this enzyme is found in peroxisomes, structures that are important for several cellular activities such as ridding the cell of toxic substances and helping to break down certain fats. Peroxisomes contain several enzymes that are imported from the internal fluid of the cell (cytosol). Enzymes that are transferred into peroxisomes have a special arrangement of building blocks (amino acids) at one end of the enzyme that serves as a shipping address. In the peroxisome, alanine-glyoxylate aminotransferase converts a compound called glyoxylate to the amino acid glycine, which is later used for making enzymes and other proteins.

primary hyperoxaluria - caused by mutations in the AGXT gene

Researchers have identified about 50 AGXT mutations that cause type 1 primary hyperoxaluria. In some type 1 primary hyperoxaluria cases, alanine-glyoxylate aminotransferase enzyme activity is partially or entirely absent because of a mutation. As a result of this enzyme shortage, glyoxylate accumulates and is converted to a compound called oxalate instead of glycine. Oxalate, in turn, combines with calcium to form calcium oxalate, which the body cannot readily eliminate. Deposits of calcium oxalate can lead to kidney stones, kidney damage or failure, and injury to other organs, which are characteristic features of primary hyperoxaluria.

In other people with type 1 primary hyperoxaluria, the alanine-glyoxylate aminotransferase enzyme is misplaced within the cell. Misplacement occurs when certain mutations combine with a natural variation (polymorphism) in the gene. In most cases, a mutation replaces the amino acid glycine with the amino acid arginine at position 170 in the enzyme (written as Gly170Arg or G170R). This mutation occurs with a polymorphism that replaces the amino acid proline with the amino acid leucine at position 11 (written as Pro11Leu or P11L). The combined effect of the mutation and the polymorphism alters the structure of alanine-glyoxylate aminotransferase and changes the cellular shipping address of the enzyme. Instead of locating in peroxisomes, the enzyme is misdelivered to mitochondria, the energy-producing centers of cells. Even though the enzyme retains some of its activity, it cannot make contact with glyoxylate, which is located in peroxisomes. As a result, glyoxylate accumulates, leading to the signs and symptoms of primary hyperoxaluria.