The functional deficit of alanine:glyoxylate aminotransferase (AGT) in
human hepatocytes leads to a rare recessive disorder named primary hyperoxaluria
type I (PH1). PH1 is characterized by the progressive accumulation and deposition of
calcium oxalate stones in the kidneys and urinary tract, leading to a life-threatening
and potentially fatal condition. In the last decades, substantial progress in the clarification
of the molecular pathogenesis of the disease have been made. They resulted in the
understanding that many mutations cause AGT deficiency by affecting the folding
pathway of the protein leading to a reduced expression level, an increased aggregation
propensity, and/or an aberrant mitochondrial localization. Thus, PH1 can be considered
a misfolding disease and possibly treated by approaches aimed at counteracting
the conformational defects of the variants. In this review, we summarize recent advances in the development
of new strategies to identify molecules able to rescue AGT folding and trafficking either by acting
as pharmacological chaperones or by preventing the mistargeting of the protein.
Keywords: Primary hyperoxaluria type I, alanine: glyoxylate aminotransferase, misfolding disease, pyridoxal 5’-phosphate,
pathogenic variants, pharmacological chaperones.
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