Drs. Kushner and Phillips have ascertained over 120 pedigrees with porphyria cutanea tarda (PCT) for their studies. This is the largest collection of patients with porphyria cutanea tarda assembled for research purposes. These investigators have established that both genetic and environmental factors contribute to the pathogenesis of PCT. Two genetic factors have been identified: mutations at the hemochromatosis locus and mutations at the uroporphyrinogen decarboxylase (URO-D) locus. Mutant hemochromatosis alleles are present in approximately half of the patients who develop porphyria cutanea tarda and about 35% have mutations of the URO-D locus. Hepatitis C virus, alcohol abuse and medicinal estrogens have been identified as environmental factors contributing to expression of the PCT phenotype. Drs, Kushner and Phillips have solved the crystal structure of human URO-D. They have identified over 20 mutations in the URO-D gene in unrelated patients with PCT and have mapped mutations to the crystal structure and determined the effects of specific mutations on protein structure and function. Using an animal model of PCT these investigators have identified a low molecular compound that acts as a specific inhibitor of URO-D. The physical characteristics of this inhibitor have been established and in preliminary studies, a similar inhibitory compound has been identified in liver cytosol from a human subject with PCT. The detection and characterization of an inhibitor of URO-D activity present in hepatocytes represents a major advance in our understanding of the molecular pathogenesis of PCT. It appears that both genetic and environmental factors come to play in generating this liver specific inhibitor. Molecular characterization on the inhibitory compound may lead to experimental treatments aimed at blocking the formation of this substance.
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