Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria
Copyright policy )Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria
Significance The genetic disease congenital erythropoietic porphyria (CEP) results from the accumulation of toxic porphyrins owing to an enzymatic uroporphyrinogen III synthase (UROS) defect. We have already shown that the UROS C73R and UROS P248Q mutants, usually associated with a severe phenotype, conserve partial intrinsic enzymatic activity but suffer from kinetic instability and premature degradation by the proteasome pathway. We now demonstrate that treatment with a clinically approved proteasome inhibitor could rescue UROS mutant expression in human erythroid cells and reverse the skin photosensitivity in homozygous Uros P248Q CEP mice. Based on our understanding of the biochemical mechanism of UROS enzymatic deficiency, these innovative results open the way for a pharmacologic treatment of CEP disease as an alternative to bone marrow transplantation.
- University of Bordeaux France
- Inserm France
- Laboratory of Excellence GR-Ex France
- French Institute of Health and Medical Research France
- University of Bordeaux France
Models, Molecular, Protein Folding, Porphyrins, Circular Dichroism, Porphyria, Erythropoietic, Blotting, Western, Mutation, Missense, Real-Time Polymerase Chain Reaction, Boronic Acids, Uroporphyrinogen III Synthetase, Bortezomib, Mice, Spectrometry, Fluorescence, Erythroid Cells, Pyrazines, Animals, Humans, Proteasome Inhibitors, DNA Primers
Models, Molecular, Protein Folding, Porphyrins, Circular Dichroism, Porphyria, Erythropoietic, Blotting, Western, Mutation, Missense, Real-Time Polymerase Chain Reaction, Boronic Acids, Uroporphyrinogen III Synthetase, Bortezomib, Mice, Spectrometry, Fluorescence, Erythroid Cells, Pyrazines, Animals, Humans, Proteasome Inhibitors, DNA Primers
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