A mouse model of familial porphyria cutanea tarda

Approximately one-third of patients with porphyria cutanea tarda (PCT), the most common porphyria in humans, inherit a single mutant allele of the uro porphyrinogen decarboxylase (URO-D) gene. PCT associated with URO-D mutatio ns is designated familial PCT. The phenotype is characterized by a photosen sitive dermatosis with hepatic accumulation and urinary excretion of uropor phyrin and hepta-carboxylic porphyrins. Most heterozygotes for URO-D mutati ons do not express a porphyric phenotype unless hepatic siderosis is presen t. Hemochromatosis gene (HFE) mutations are frequently found when the pheno type is expressed. We used homologous recombination to disrupt one allele o f murine URO-D. URO-D+/- mice had half-wild type (wt) URO-D protein and enz ymatic activity in all tissues but did not accumulate hepatic porphyrins, i ndicating 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, an d 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 red uced to 14% of wt. These data indicate that iron overload alone is sufficie nt to reduce URO-D activity to rate-limiting levels in URO-D+/- mice. The U RO-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 .