Uroporphyrinogen III synthase knock-in mice have the human congenital erythropoietic porphyria phenotype, including the characteristic light-induced cutaneous lesions.
Congenital erythropoietic porphyria (CEP), an autosomal recessive inborn error, results from the deficient but not absent activity of uroporphyrinogen III synthase (URO-synthase), the fourth enzyme in the heme biosynthetic pathway. The major clinical manifestations include severe anemia, erythrodontia, and disfiguring cutaneous involvement due to the accumulation of phototoxic porphyrin I isomers. Murine models of CEP could facilitate studies of disease pathogenesis and the evaluation of therapeutic endeavors. However, URO-synthase null mice were early embryonic lethals. Therefore, knock-in mice were generated with three missense mutations, C73R, V99A, and V99L, which had in vitro-expressed activities of 0.24%, 5.9%, and 14.8% of expressed wild-type activity, respectively. Homozygous mice for all three mutations were fetal lethals, except for mice homozygous for a spontaneous recombinant allele, V99A(T)/V99A(T), a head-to-tail concatemer of three V99A targeting constructs. Although V99A(T)/V99A(T) and C73R/V99A(T) mice had approximately 2% hepatic URO-synthase activity and normal hepatic microsomal heme and hemoprotein levels, they had 20% and 13% of wild-type activity in erythrocytes, respectively, which indicates that sufficient erythroid URO-synthase was present for fetal development and survival. Both murine genotypes showed marked porphyrin I isomer accumulation in erythrocytes, bone, tissues, and excreta and had fluorescent erythrodontia, hemolytic anemia with reticulocytosis and extramedullary erythropoiesis, and, notably, the characteristic light-induced cutaneous involvement. These mice provide insight into why CEP is an erythroid porphyria, and they should facilitate studies of the disease pathogenesis and therapeutic endeavors for CEP.
Bishop
David F
DF
Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Johansson
Annika
A
Phelps
Robert
R
Shady
Amr A
AA
Ramirez
Maria C M
MC
Yasuda
Makiko
M
Caro
Andres
A
Desnick
Robert J
RJ
D000818:Animals; D006418:Heme / Q000378:metabolism; D006801:Humans; D008027:Light / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D010641:Phenotype; D017092:Porphyria, Erythropoietic / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D011166:Porphyrins / Q000378:metabolism; D012871:Skin Diseases / Q000209:etiology* / Q000503:physiopathology; D014576:Uroporphyrinogen III Synthetase / Q000235:genetics / Q000502:physiology*
D011166:Porphyrins; D006418:Heme; D014576:Uroporphyrinogen III Synthetase