AGXT gene is located at the telomeric end of the long arm of chromosome 2 at 2q36-37 and spans 100 kb of genomic DNA with a coding sequence consisting of 11 exons. The AGXT gene is expressed only in liver tissue and helps in the intracellular localization in hepatocyte is the peroxisomes where its substrate, glyoxylate, is synthesized. Human AGT is a homodimeric protein; each subunit composes of 392 amino acids with a molecular mass of about 43 KDa. Each subunit consists of three structural and functional domains: the N-terminal domain is encoded by exon 1, the active site and dimerization interface is encoded by exons 1, 2, 3, 4, 5, 6, 7 and 8, and the C terminal domain is encoded by exons 9, 10 and 11. This domain contains the principal and ancillary peroxisomal targeting information.
AGXT gene exists on two haplotypes: the major and the minor allele. The minor allele is characterized by the presence of the combination of three polymorphisms including: P11L in exon 1, I340M in exon 10 and a 74 bp duplication in intron 1, whereas the absence of these three polymorphisms is defined the major allele. Unlike most polymorphisms in most genes, the P11L polymorphism has a significant effect on the properties of AGT protein. The most important effect is its ability to act as a modifier to some AGXT mutations when it exists in cis with these mutations. It was predicted that the most common mutation (G170R) has no effect when this polymorphisms is absent.
To date, over 65 mutations have been identified in the AGXT gene, leading to cause PH1 disease. These mutations from all types, but about 50% of the mutations are missense mutations. Some of these mutations including the common mutations (G170R, I244T, F152I) are inherited with the minor allele especially with the P11L polymorphism. These three mutations account for more than 45% of PH1 mutations. However, the mutations which occur on the background of the major allele are more heterogeneous, they appear to be private and family-specific. The mutations causing PH1 have been associated with a wide variety of effects on AGT protein, including loss of catalytic activity, loss of immunoreactive AGT protein. The most unusual enzymatic phenotype which found in one third of PH1 patients is associated with the most common mutation (G170A). This mutation resulted in mistargeted 90% of AGT from its normal intracellular location in the peroxisomes to mitochondria. Although AGT remains catalytically active in the mitochondria, it is metabolically ineffective, because its substrate, glyoxylate, is synthesized in the peroxisomes.
