title: A mouse model of familial porphyria cutanea tarda.
abstract: Approximately one-third of patients with porphyria cutanea tarda (PCT), the most common porphyria in humans, inherit a single mutant allele of the uroporphyrinogen decarboxylase (URO-D) gene. PCT associated with URO-D mutations is designated familial PCT. The phenotype is characterized by a photosensitive dermatosis with hepatic accumulation and urinary excretion of uroporphyrin and hepta-carboxylic porphyrins. Most heterozygotes for URO-D mutations do not express a porphyric phenotype unless hepatic siderosis is present. Hemochromatosis gene (HFE) mutations are frequently found when the phenotype is expressed. We used homologous recombination to disrupt one allele of murine URO-D. URO-D(+/-) mice had half-wild type (wt) URO-D protein and enzymatic activity in all tissues but did not accumulate hepatic porphyrins, indicating that half-normal URO-D activity is not rate limiting. When URO-D(+/-) mice were injected with iron-dextran and given drinking water containing delta-aminolevulinic acid for 21 days, hepatic porphyrins accumulated, and hepatic URO-D activity was reduced to 20% of wt. We bred mice homozygous for an HFE gene disruption (HFE(-/-)) to URO-D(+/-) mice, generating mice with the URO-D(+/-)/HFE(-/-) genotype. These animals developed a porphyric phenotype by 14 weeks of age without ALA supplementation, and URO-D activity was reduced to 14% of wt. These data indicate that iron overload alone is sufficient to reduce URO-D activity to rate-limiting levels in URO-D(+/-) mice. The URO-D(+/-) mouse serves as an excellent model of familial PCT and affords the opportunity to define the mechanism by which iron influences URO-D activity.
authors.affiliation: Department of Medicine, University of Utah, School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Phillips
authors.forename: L K
authors.initials: LK
authors.lastname: Jackson
authors.forename: M
authors.initials: M
authors.lastname: Bunting
authors.forename: M R
authors.initials: MR
authors.lastname: Franklin
authors.forename: K R
authors.initials: KR
authors.lastname: Thomas
authors.forename: J E
authors.initials: JE
authors.lastname: Levy
authors.forename: N C
authors.initials: NC
authors.lastname: Andrews
authors.forename: J P
authors.initials: JP
authors.lastname: Kushner
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D003001:Cloning, Molecular; D003305:Coproporphyrinogens / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D018390:Gene Targeting; D005838:Genotype; D006432:Hemochromatosis / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000032:analysis; D007505:Iron-Dextran Complex / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017119:Porphyria Cutanea Tarda / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D011166:Porphyrins / Q000032:analysis / Q000652:urine; D013234:Stem Cells / Q000378:metabolism; D014575:Uroporphyrinogen Decarboxylase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014577:Uroporphyrinogens / Q000737:chemistry / Q000378:metabolism
chemical_list: D003305:Coproporphyrinogens; D004791:Enzyme Inhibitors; D011166:Porphyrins; D014577:Uroporphyrinogens; C028026:coproporphyrinogen III; D000622:Aminolevulinic Acid; D007505:Iron-Dextran Complex; D007501:Iron; D014575:Uroporphyrinogen Decarboxylase