The molecular basis of alanine: glyoxylate aminotransferase mistargeting: the most common single cause of primary hyperoxaluria type 1.

The autosomal recessive disease primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver-specific intermediary metabolic enzyme alanine:glyoxylate aminotransferase (AGT). In a third of all Caucasian PH1 patients, disease in caused by an unparalleled intracellular phenomenon in which AGT is mistargeted from one group of intracellular organelles (the peroxisomes) to another (the mitochondria) where it is unable to work properly. The aberrant localisation of AGT in PH1 is caused by the combination of a common Pro 11-->Leu amino acid polymorphism which generates a functionally weak mitochondrial targeting signal (MTS) and a rare Gly170-->Arg mutation which in combination with the Pro11-->Leu polymorphism enhances the functional efficiency of this MTS by slowing AGT folding and dimerization. Elucidation of the molecular basis of AGT mistargeting not only provides an explanation for the mode of action of the most common mutation found in PH1, but also highlights the different structural requirements for protein import into peroxisomes and mitochondria.