title: A knock-in mouse model of congenital erythropoietic porphyria.
abstract: Congenital erythropoietic porphyria (CEP) is a recessive autosomal disorder characterized by a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. The severity of the disease, the lack of specific treatment except for allogeneic bone marrow transplantation, and the knowledge of the molecular lesions are strong arguments for gene therapy. An animal model of CEP has been designed to evaluate the feasibility of retroviral gene transfer in hematopoietic stem cells. We have previously demonstrated that the knockout of the Uros gene is lethal in mice (Uros(del) model). This work describes the achievement of a knock-in model, which reproduces a mutation of the UROS gene responsible for a severe UROS deficiency in humans (P248Q missense mutant). Homozygous mice display erythrodontia, moderate photosensitivity, hepatosplenomegaly, and hemolytic anemia. Uroporphyrin (99% type I isomer) accumulates in urine. Total porphyrins are increased in erythrocytes and feces, while Uros enzymatic activity is below 1% of the normal level in the different tissues analyzed. These pathological findings closely mimic the CEP disease in humans and demonstrate that the Uros(mut248) mouse represents a suitable model of the human disease for pathophysiological, pharmaceutical, and therapeutic purposes.
authors.affiliation: INSERM E217, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France. cecil.ged@u-bordeaux.fr
authors.forename: C
authors.initials: C
authors.lastname: Ged
authors.forename: M
authors.initials: M
authors.lastname: Mendez
authors.forename: E
authors.initials: E
authors.lastname: Robert
authors.forename: M
authors.initials: M
authors.lastname: Lalanne
authors.forename: I
authors.initials: I
authors.lastname: Lamrissi-Garcia
authors.forename: P
authors.initials: P
authors.lastname: Costet
authors.forename: J Y
authors.initials: JY
authors.lastname: Daniel
authors.forename: P
authors.initials: P
authors.lastname: Dubus
authors.forename: F
authors.initials: F
authors.lastname: Mazurier
authors.forename: F
authors.initials: F
authors.lastname: Moreau-Gaudry
authors.forename: H
authors.initials: H
authors.lastname: de Verneuil
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D015316:Genetic Therapy; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D017092:Porphyria, Erythropoietic / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D014576:Uroporphyrinogen III Synthetase / Q000235:genetics* / Q000378:metabolism; D014578:Uroporphyrins / Q000378:metabolism
chemical_list: D014578:Uroporphyrins; C034103:uroporphyrin I; D014576:Uroporphyrinogen III Synthetase