A MUTATION (G281E) OF THE HUMAN UROPORPHYRINOGEN DECARBOXYLASE GENE CAUSES BOTH HEPATOERYTHROPOIETIC PORPHYRIA AND OVERT FAMILIAL PORPHYRIA-CUTANEA-TARDA - BIOCHEMICAL AND GENETIC-STUDIES ON SPANISH PATIENTS

Hepatoerythropoietic porphyria is a severe cutaneous porphyria caused by deficiency of uroporphyrinogen decarboxylase and is considered to b e the homozygous form of familial (type II) porphyria cutanea tarda. T o elucidate further the relation between these conditions, we studied five Spanish families with hepatoerythropoietic porphyria and nine unr elated Spanish patients with familial porphyria cutanea tarda. Immunor eactive and catalytic uroporphyrinogen decarboxylase was decreased by greater than 95% in the five patients with hepatoerythropoietic porphy ria. Hepatic uroporphyrinogen decarboxylase activity was decreased to 22% of normal. Four patients were homozygous for a mutation (G281E) or iginally identified in a Tunisian family; the fifth patient was a comp ound heterozygote for this mutation. The calculated carrier frequency for G281E in Spain is one in 1800. None of the nine familial porphyria cutanea tarda patients carried the G281E mutation. However, one G281E heterozygote in a family with hepatoerythropoietic porphyria had over t porphyria cutanea tarda. These findings suggest that the G281E mutat ion is functionally less severe than erythrocyte measurements indicate , that its clinical penetrance is very low in heterozygotes, and that, for this particular mutation, hepatoerythropoietic porphyria is the h omozygous form of familial porphyria cutanea tarda.