Genetics and pathogenesis of human uroporphyrinogen decarboxylase defects

Abstract

Two types of human porphyria, porphyria cutanea tarda (PCT) and hepatoerythropoietic porphyria (HEP), result from partial deficiency of uroporphyrinogen decarboxylase (UROD). About 20% of patients with PCT have a 50% decrease in UROD concentration in all tissues that is inherited as an autosomal dominant trait with low penetrance (type II PCT). Both this condition and its postulated homozygous counterpart, HEP, show genetic heterogeneity. Identification of a form of familial PCT in which the activity and concentration of erythrocyte UROD is normal, as in type I or sporadic PCT, suggests than an autosomal gene, not necessarily at the UROD locus, may be important in determining the onset of type I PCT. Clinically overt PCT results from a liver-specific process that causes reversible inactivation of UROD and which may be iron dependent. The predisposition to develop PCT in response to common hepatotoxic agents and other acquired factors may be determined by interaction between genes that control the concentration of active UROD in cells and genes that facilitate the inactivation process.