Molecular etiology of primary hyperoxaluria type 1: new directions for treatment.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal-recessive disorder caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase (AGT). AGT deficiency results in increased synthesis and excretion of the metabolic end-product oxalate and deposition of insoluble calcium oxalate in the kidney and urinary tract. Classic treatments for PH1 have tended to address the more distal aspects of the disease process (i.e. the symptoms rather than the causes). However, advances in the understanding of the molecular etiology of PH1 over the past decade have shifted attention towards the more proximal aspects of the disease process (i.e. the causes rather than the symptoms). The determination of the crystal structure of AGT has enabled the effects of some of the most important missense mutations in the AGXT gene to be rationalised in terms of AGT folding, dimerization and stability. This has opened up new possibilities for the design pharmacological agents that might counteract the destabilizing effects of these mutations and which might be of use for the treatment of a potentially life-threatening and difficult-to-treat disease.