Ferrochelatase (FECH) activity is decreased in erythropoietic protoporphyria (EPP), causing increased production and excretion of protoporphyrin. This study examined whether the level of expression of the nonmutant FECH allele is a determinant of phenotype in a mouse model of EPP that carries a heterozygous deletion of exon 10 in FECH. Two mice strains that had a two-fold difference in FECH mRNA levels in bone marrow and liver (low expressing C3H/HeJ and high expressing CBA/J) were used to establish congenic strains containing the mutation. Erythrocyte protoporphyrin levels in C3H/HeJ heterozygous mice were significantly higher than in their wildtype littermates, whereas levels in CBA/J heterozygous mice did not differ significantly from their wildtype littermates. Biliary excretion of protoporphyrin was also significantly higher in C3H/HeJ heterozygous mice. The levels of normal FECH mRNA in bone marrow measured by real time PCR were 138 +/- 30 copies per ug total RNA in C3H/HeJ +/- mice, 320 +/- 59 in C3H/HeJ +/+ mice and 634 +/- 38 in CBA/J +/+ mice. Levels in liver tissue of the mice differed significantly in the same pattern. Thus, the level of expression of the nonmutant FECH allele is a determinant of phenotype in a mouse model of EPP as has been demonstrated in human EPP.