RGD Reference Report - A mouse model of familial porphyria cutanea tarda. - Rat Genome Database

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A mouse model of familial porphyria cutanea tarda.

Authors: Phillips, JD  Jackson, LK  Bunting, M  Franklin, MR  Thomas, KR  Levy, JE  Andrews, NC  Kushner, JP 
Citation: Phillips JD, etal., Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):259-64.
RGD ID: 7207253
Pubmed: PMID:11134514   (View Abstract at PubMed)
PMCID: PMC14578   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.011481398   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
porphyria cutanea tarda  ISOHfe (Mus musculus)7207253; 7207253 RGD 
porphyria cutanea tarda  IMP 7207253 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hfe  (homeostatic iron regulator)

Genes (Mus musculus)
Hfe  (homeostatic iron regulator)

Genes (Homo sapiens)
HFE  (homeostatic iron regulator)


Additional Information