Selected Exonic Sequencing of the AGXT Gene Provides a Genetic Diagnosis in 50% of Patients with Primary Hyperoxaluria Type I (Molecular Diagnostics and Genetics‪)‬

Primary hyperoxaluria type 1 (PH1) [1] (OMIM 259900) is an autosomal recessive disorder of glyoxylate metabolism caused by deficiency of alanine:glyoxylate aminotransferase (AGT; EC 2.6.1.44). AGT is a pyridoxine 5'-phosphate-dependent enzyme that is liver specific (1) and usually located within the peroxisome (2). This intracellular location allows efficient removal of potentially toxic glyoxylate via conversion to glycine. In the absence of AGT, glyoxylate accumulates and is converted to oxalate, which is excreted by the kidney and leads to hyperoxaluria. Insoluble calcium oxalate salts crystallize in the kidney, leading to urolithiasis and nephrocalcinosis, thereby decreasing renal function, and ultimately leading to end-stage renal failure and systemic oxalosis if treatment is not initiated (3). AGXT, [2] the gene encoding the AGT protein, comprises 11 exons over 10 kb and maps to chromosome 2q37.3 (4). The cDNA contains an open reading frame of 1179 nucleotides encoding a 392-residue polypeptide that homodimerizes to yield a protein of 86 kDa (5). Wild-type AGT exists as 2 main genetic variants, with either a proline (major allele) or leucine (minor allele) residue at position 11 in the protein sequence (6). The minor AGXT allele has a frequency of 15%-20% in European and North American populations (6) but a much higher frequency, ~50%, among PH1 patients (7). The Leu11 variant has several measurable effects on the properties of recombinant AGT protein expressed in vitro. The Leu11 variant encodes a protein with ~50% of the activity of the more common Pro11 allele, and the Leu11 protein has a decreased dimerization rate at increased temperatures (8). There is also evidence that the presence of Leu11 potentiates the effect of some mutations (8, 9).