ArticleProceedings of the National Academy of Sciences of the United States of America2013
Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 38 citations in OpenAlex.
- [Two siblings with congenital erythropoietic porphyria in one family: case report and literature review].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2025Review
- The Hepatic Porphyrias: Revealing the Complexities of a Rare Disease.Seminars in liver disease · 2023Review
- Metabolic Landscape of the Mouse Liver by QuantitativeHepatology (Baltimore, Md.) · 2021Article
- Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria.Journal of personalized medicine · 2021Article
- Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models.Scientific reports · 2021Article
- Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators.International journal of molecular sciences · 2021Review
- Acute Hepatic Porphyria: Pathophysiological Basis of Neuromuscular Manifestations.Frontiers in neuroscience · 2021Review
- Abnormal concentration of porphyrins in serum from COVID-19 patients.British journal of haematology · 2020Article
- Murine models of the human porphyrias: Contributions toward understanding disease pathogenesis and the development of new therapies.Molecular genetics and metabolism · 2019Review
- Congenital erythropoietic porphyria: Recent advances.Molecular genetics and metabolism · 2019Review
- Hereditary tyrosinemia type I-associated mutations in fumarylacetoacetate hydrolase reduce the enzyme stability and increase its aggregation rate.The Journal of biological chemistry · 2019Article
- Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury.Cellular and molecular gastroenterology and hepatology · 2019Review
- [Congenital erythropoietic porphyria : An update].Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete · 2016Review
- Bortezomib alleviates drug-induced liver injury by regulating CYP2E1 gene transcription.International journal of molecular medicine · 2016Article
- 129-Derived Mouse Strains Express an Unstable but Catalytically Active DNA Polymerase Iota Variant.Molecular and cellular biology · 2015Article
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in massive porphyrin accumulation in blood cells, which is responsible for hemolytic anemia and skin photosensitivity. Among the missense mutations actually described up to now in CEP patients, the C73R and the P248Q mutations lead to a profound UROS deficiency and are usually associated with a severe clinical phenotype. We previously demonstrated that the UROS(C73R) mutant protein conserves intrinsic enzymatic activity but triggers premature degradation in cellular systems that could be prevented by proteasome inhibitors. We show evidence that the reduced kinetic stability of the UROS(P248Q) mutant is also responsible for increased protein turnover in human erythroid cells. Through the analysis of EGFP-tagged versions of UROS enzyme, we demonstrate that both UROS(C73R) and UROS(P248Q) are equally destabilized in mammalian cells and targeted to the proteasomal pathway for degradation. We show that a treatment with proteasomal inhibitors, but not with lysosomal inhibitors, could rescue the expression of both EGFP-UROS mutants. Finally, in CEP mice (Uros(P248Q/P248Q)) treated with bortezomib (Velcade), a clinically approved proteasome inhibitor, we observed reduced porphyrin accumulation in circulating RBCs and urine, as well as reversion of skin photosensitivity on bortezomib treatment. These results of medical importance pave the way for pharmacologic treatment of CEP disease by preventing certain enzymatically active UROS mutants from early degradation by using proteasome inhibitors or chemical chaperones.
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