Inheritance in erythropoietic protoporphyria: A common wild-type ferrochelatase allelic variant with low expression accounts for clinical manifestation

Erythropoietic protoporphyria (EPP) is a rare autosomal dominant disorder o f heme biosynthesis characterized by partial decrease in ferrochelatase (FE CH; EC 4.99.1.1) activity with protoporphyrin overproduction and consequent painful skin photosensitivity and rarely liver disease. EPP is normally in herited in an autosomal dominant pattern with low clinical penetrance; the many different mutations that have been identified are restricted to one FE CH allele, with the other one being free of any mutations. However, clinica l manifestations of dominant EPP cannot be simply a matter of FECH haploins ufficiency, because patients have enzyme levels that are lower than the exp ected 50%. From RNA analysis in one family with dominant EPP, we recently s uggested that clinical expression required coinheritance of a normal FECH a llele with low expression and a mutant FECH allele. We now show that (1) co inheritance of a FECH gene defect and a wild-type low-expressed allele is g enerally involved in the clinical expression of EPP; (2) the low-expressed allelic variant was strongly associated with a partial 5' haplotype [-251G IVS1-23T IVS2 mu satA9] that may be ancestral and was present in an estimat ed 10% of a control group of Caucasian origin; and (3) haplotyping allows t he absolute risk of developing the disease to be predicted for those inheri ting FECH EPP mutations. EPP may thus be considered as an inherited disorde r that does not strictly follow recessive or dominant rules. It may represe nt a model for phenotype modulation by mild variation in expression of the wild-type allele in autosomal dominant diseases. (C) 1999 by The American S ociety of Hematology.