Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda

Porphyria cutanea tarda is a skin disease caused by photosensitization by p orphyrins whose accumulation is caused by deficiency of hepatic uroporphyri n- ogen decarboxylase activity. Mutations in the uroporphyrinogen decarboxy lase gene are present in the low-penetrant, autosomal dominant familial for m but not in the commoner sporadic form of porphyria cutanea tarda. We have investigated the relationship between age of onset of skin lesions and mut ations (C282Y, H63D) in the hemochromatosis gene in familial (19 patients) and sporadic porphyria cutanea tarda (65 patients). Familial porphyria cuta nea tarda was identified by mutational analysis of the uroporphyrinogen dec arboxylase gene. Five previously described and eight novel mutations (A80S, R144P, L216Q, E218K, L282R, G303S, 402-403delGT, IVS2 + 2 delTAA) were ide ntified. Homozygosity for the C282Y hemochromatosis mutation was associated with an earlier onset of skin lesions in both familial and sporadic porphy ria cutanea tarda, the effect being more marked in familial porphyria cutan ea tarda where anticipation was demonstrated in family studies. Analysis of the frequencies of hemochromatosis genotypes in each type of porphyria cut anea tarda indicated that C282Y homozygosity is an important susceptibility factor in both types but suggested that heterozygosity for this mutation h as much less effect on the development of the disease.