Hypermethylation of the wild-type ferrochelatase allele is closely associated with severe liver complication in a family with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by cellular decreases in ferrochelatase (FECH) activity. Clinical expression of this disorder usually requires coinheritance of a mutant FECH allele and a normal FECH allele expressed at a low level. In this study, we investigated the methylation status of a normal, but poorly expressed, FECH gene in a single Japanese family with EPP. In this family, the proband died from liver failure, whereas the mother and sister exhibited overt EPP with mild liver dysfunction. A splicing mutation (IVS9+1g-->a) in the FECH gene, which produces a mutant FECH transcript lacking exon 9, was detected in the maternal allele of the proband and his sister. All subjects, including the father, who did not exhibit EPP, possessed the IVS3-48c/c genotype. This allele increases the proportion of aberrantly spliced mRNA, resulting in reduced FECH activity. Normal FECH transcripts were, however, detected in the mother and sister, but not in the proband. The CpG sites in the region from bases -78 to -31 were partially methylated in the proband and his father, but not in his mother or sister. Additionally, CpG methylation within this region reduced transcription of the FECH gene. These results suggest that whereas the combination of a maternal IVS9+1a allele and a paternal IVS3-48c allele results in overt EPP, CpG methylation of the FECH gene promoter, likely inherited from the father, increases the severity of EPP, leading to fatal liver failure, as seen in the proband.