Congenital Erythropoietic Porphyria: Characterization of Murine Models of the Severe Common (C73R/C73R) and Later-Onset Genotypes
Congenital Erythropoietic Porphyria: Characterization of Murine Models of the Severe Common (C73R/C73R) and Later-Onset Genotypes
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DOI：
10.2119/molmed.2010.00258
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发表时间：
2011-07-01
影响因子：
5.7
通讯作者：
Desnick, Robert J.
中科院分区：
文献类型：
--
作者：
Bishop, David F.;Clavero, Sonia;Desnick, Robert J.
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 (similar to 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 mu mol/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 mu mol/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. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org
