Molecular genetics of erythropoietic protoporphyria

Abstract

Erythropoietic protoporphyria (EPP) is caused by decreased activity of the enzyme ferrochelatase and is characterized by burning photosensitivity commencing in childhood. From 1-10% of patients develop potentially fatal protoporphyric hepatic failure. The gene for ferrochelatase has been cloned, sequenced and mapped to the long arm of chromosome 18. EPP is genetically very heterogeneous and 24 different mutations in 27 unrelated patients have been published. In the majority of families co-inheritance of a mutant ferrochelatase allele from one parent and a low-output 'normal' ferrochelatase allele from the other parent is required for disease expression. The molecular basis, if any, of protoporphyric hepatic failure has not yet been resolved. Gene therapy experiments have been completed in vitro and are in progress in an animal model of EPP. In conclusion, molecular genetic investigation of EPP has increased our understanding of its pathogenesis and inheritance. Why some EPP patients develop hepatic failure is still unanswered. Gene therapy of EPP patients may become possible in the future.