MODULATION OF THE PHENOTYPE IN DOMINANT ERYTHROPOIETIC PROTOPORPHYRIABY A LOW EXPRESSION OF THE NORMAL FERROCHELATASE ALLELE

Erythropoietic protoporphyria (EPP) is a monogenic inherited disorder of the heme biosynthetic pathway due to ferrochelatase (FC) deficiency . EPP is generally considered to be transmitted as an autosomal domina nt disease with incomplete penetrance, although autosomal recessive in heritance has been documented at the enzymatic and molecular level in some families. In the dominant form of EPP, statistical analysis of FC activities documented a significantly lower mean value in patients th an in asymptomatic carriers, suggesting a more complex mode of inherit ance. To account for these findings, we rested a multiallelic inherita nce model in one EPP family in which the enzymatic data were compatibl e with this hypothesis. In this EPP family, the specific FC gene mutat ion was an exon 10 skipping (Delta Ex10), resulting from a G deletion within the exon 10 consensus splice donor site. The segregation of al FC alleles within the family was followed using the Delta Ex10 mutatio n and a new intragenic dimorphism (1520 C/T). mRNAs transcribed from e ach FC allele were then subjected to relative quantification by a prim er extension assay and to absolute quantification by a ribonuclease pr otection assay. The data support the hypothesis that in this family th e EPP phenotype results from the coinheritance of a low output normal FC allele and a mutant Delta Ex10 allele.