Abstract
Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity and photomutilation. Currently there is no specific treatment for CEP, except bone marrow transplantation, and there is an unmet need for treating this orphan disease. Fluorescent porphyrins cause protein aggregation, which led us to hypothesize that uroporphyrin-I accumulation leads to protein aggregation and CEP-related bone phenotype. We developed a zebrafish model that phenocopies features of CEP. As in human patients, uroporphyrin-I accumulated in the bones of zebrafish, leading to impaired bone development. Furthermore, in an osteoblast-like cell line, uroporphyrin-I decreased mineralization, aggregated bone matrix proteins, activated endoplasmic reticulum stress and disrupted autophagy. Using high-throughput drug screening, we identified acitretin, a second-generation retinoid, and showed that it reduced uroporphyrin-I accumulation and its deleterious effects on bones. Our findings provide a new CEP experimental model and a potential repurposed therapeutic.
Highlights
Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/ coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase
Using high-throughput drug screening, we identified acitretin, a 2 nd generation retinoid, as an effective drug that mitigates some of the harmful effects of uro-I in zebrafish and Saos-2 cells
Light is unlikely to reach deep internal tissues, which are affected in CEP
Summary
Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/ coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Fluorescent porphyrins cause protein aggregation, which led us to hypothesize that uroporphyrin-I accumulation leads to protein aggregation and CEP-related bone phenotype. CEP is rare, with ~ 250 cases reported to d ate[4,5] It is autosomal recessive, and associated with reduced UROS activity (5% of normal) and consequent accumulation of uro/coproporphyrin-I (uro/copro-I) in bone marrow, erythrocytes, plasma, and increased uro/copro-I excretion in urine and stool[1,3,5,6]. Fluorescent porphyrin accumulation in porphyria causes organelle specific protein oxidation and aggregation through mechanisms that involve type-II photosensitive reactions and secondary oxidative s tress[10,11,12,13,14,15,16,17]. Using high-throughput drug screening, we identified acitretin, a 2 nd generation retinoid, as an effective drug that mitigates some of the harmful effects of uro-I in zebrafish and Saos-2 cells
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