title: Congenital erythropoietic porphyria: characterization of murine models of the severe common (C73R/C73R) and later-onset genotypes.
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.
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA. david.bishop@mssm.edu
authors.forename: David F
authors.initials: DF
authors.lastname: Bishop
authors.forename: Sonia
authors.initials: S
authors.lastname: Clavero
authors.forename: Narla
authors.initials: N
authors.lastname: Mohandas
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D007668:Kidney / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D010641:Phenotype; D017092:Porphyria, Erythropoietic / Q000201:enzymology / Q000235:genetics*; D011166:Porphyrins / Q000378:metabolism; D013154:Spleen / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014576:Uroporphyrinogen III Synthetase / Q000235:genetics* / Q000378:metabolism
chemical_list: D011166:Porphyrins; D014576:Uroporphyrinogen III Synthetase