¹Division of Gastroenterology/Hepatology and ²Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama

Abstract

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.