Effect of pharmacochaperones in AGT mistargeting

Abstract

Primary hyperoxalurias (PHs) are rare inborn errors of glyoxylate metabolism characterized by excessive synthesis and excretion of the metabolic end-product oxalate and the progressive accumulation of insoluble calcium oxalate in the kidney and urinary tract. About one third of the cases of Primary hyperoxaluria type 1 (PH1) is due to a unique protein trafficking defect in which AGT is mistargeted from peroxisomes to mitochondria, where it is metabolically useless. Pharmacological chaperones have been shown to correct protein misfolding in several genetic diseases. We aimed to test the effect of B6-vitamers (PM, PL, PN) on AGT mitochondrial mistargeting in primary culture of hepatocytes from AGT*LRM mice, which express the mutant mistargeting AGT protein (with mutation G170R in the minor haplotype of human AGT). Using image analysis tools and statistics coefficient to quantify the degree of “AGT mistargeting”.