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.