Congenital Erythropoietic Porphyria: Characterization of Murine Models of the Severe Common (C73R/C73R) and Later-Onset Genotypes

David F Bishop,Narla Mohandas,Sonia Clavero,Robert J Desnick

doi:10.2119/molmed.2010.00258

Abstract

Congenital erythropoietic porphyria (CEP) is an autosomal recessive disorder due to the deficient activity of uroporphyrinogen III synthase (UROS). Knock-in mouse models were generated for the common, hematologically severe human genotype, C73R/C73R, and milder genotypes (C73R/V99L and V99L/V99L). The specific activities of the UROS enzyme in the livers and erythrocytes of these mice averaged approximately 1.2%, 11% and 19% of normal, respectively. C73R/C73R mice that survived fetal life to weaning age (~12%) had a severe microcytic hypochromic anemia (hemoglobin 7.9 g/dL, mean cellular volume 26.6 fL, mean cellular hemoglobin content 27.4 g/dL, red cell distribution width 37.7%, reticulocytes 19%) and massively accumulated isomer I porphyrins (95, 183 and 44 μmol/L in erythrocytes, spleen and liver, respectively), but a nearly normal lifespan. In adult C73R/C73R mice, spleen and liver weights were 8.2- and 1.5-fold increased, respectively. C73R/V99L mice were mildly anemic (hemoglobin was 14.0 g/dL and mean cellular hemoglobin was 13.3), with minimally accumulated porphyrins (0.10, 5.54 and 0.58 μmol/L in erythrocytes, spleen and liver, respectively), whereas adult V99L/V99L mice were normal. Of note, even the mildest genotype, V99L/V99L, exhibited porphyria in utero, which disappeared by 2 months of age. These severe and mild mouse models inform therapeutic interventions and permit further investigation of the porphyrin-induced hematopathology, which leads to photo-induced cutaneous lesions. Of significance for therapeutic intervention, these mouse models suggest that only 11% of wild-type activity might be needed to reverse the pathology in CEP patients.

Highlights

Congenital erythropoietic porphyria (CEP; MIM 263700) is an autosomal recessive disorder of heme biosynthesis due to the markedly deficient, but not absent, activity of uroporphyrinogen III synthase (UROS; EC 4.2.1.75) and the accumulation of nonphysiological porphyrinogen I isomers [1,2,3]
In CEP, the enzymatic deficiency leads to the nonenzymatic conversion of hydroxymethylbilane to uroporphyrinogen I, which is converted to coproporphyrinogen I with oxidation to uroporphyrin I (URO I) and coproporphyrin I (COPRO I), which cannot be further metabolized
The URO I and COPRO I isomers primarily accumulate in the erythron, where heme biosynthesis is most active, and erythroid cell lysis and/or fragmentation results in high levels of these porphyrins in the circulation, from which they are accumulated in the skin, tissues and bones and are excreted in the urine and feces

Summary

Introduction

Congenital erythropoietic porphyria (CEP; MIM 263700) is an autosomal recessive disorder of heme biosynthesis due to the markedly deficient, but not absent, activity of uroporphyrinogen III synthase (UROS; EC 4.2.1.75) and the accumulation of nonphysiological porphyrinogen I isomers [1,2,3]. In CEP, the enzymatic deficiency leads to the nonenzymatic conversion of hydroxymethylbilane to uroporphyrinogen I, which is converted to coproporphyrinogen I with oxidation to uroporphyrin I (URO I) and coproporphyrin I (COPRO I), which cannot be further metabolized. The URO I and COPRO I isomers primarily accumulate in the erythron, where heme biosynthesis is most active, and erythroid cell lysis and/or fragmentation results in high levels of these porphyrins in the circulation, from which they are accumulated in the skin, tissues and bones and are excreted in the urine and feces. The variation in clinical severity depends on the level of residual UROS activity, and genotype/phenotype correlations have been reported [5]. CEP-like cutaneous symptoms and urinary excretion of URO I and COPRO I have been reported in patients who were diagnosed with myelodysplastic syndrome [9,10]. The etiology of this acquired form of CEP has not been determined, nor have there been any reports of UROS or GATA1 gene sequence mutations in these patients [11]

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