[Frontiers in Bioscience 17, 621-634, January 1, 2012]

Molecular insights into primary hyperoxaluria Type I pathogenesis

Barbara Cellini1, Elisa Oppici1, Alessandro Paiardini2, Riccardo Montioli1

1Department of Life Sciences and Reproduction, Section of Biological Chemistry, University of Verona, Strada Le Grazie 8 37134 Verona, Italy, 2Department of Biochemical Sciences, A. Rossi Fanelli, University, La Sapienza, 00185 Roma, Italy

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Primary Hyperoxaluria Type I
4. Biochemical properties of normal AGT
5. Effects of the polymorphic mutations P11L and I340M on the AGT functional and structural properties.
6. Loss of AGT catalytic activity: the G82E variant.
7. Loss of both AGT catalytic activity and immunoreactivity: the Gly41 variants
8. Mistargeting of AGT: the F152I-Mi and the G170R-Mi variants
9. Acknowledgements
10. References

1. ABSTRACT

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder of glyoxylate metabolism caused by the deficiency of liver peroxisomal alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme. The PH1 pathogenesis is mostly due to single point mutations (more than 150 so far identified) on the AGXT gene, and is characterized by a marked heterogeneity in terms of genotype, enzymatic and clinical phenotypes. This article presents an up to date review of selected aspects of the biochemical properties of the two allelic forms of AGT and of some PH1-causing variants. These recent discoveries highlight the effects at the protein level of the pathogenic mutations, and, together with previous cell biology and clinical data, (i) improve the understanding of the molecular basis of PH1 pathogenesis, and (ii) help to delineate perspectives for predicting the response to pyridoxine treatment or for suggesting new strategies for PH1 patients bearing the analyzed mutations.