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.
Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.
David F
DF
Bishop
Annika
A
Johansson
Robert
R
Phelps
Amr A
AA
Shady
Maria C M
MC
Ramirez
Makiko
M
Yasuda
Andres
A
Caro
Robert J
RJ
Desnick
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