A new ferrochelatase mutation combined with low expression alleles in a Japanese patient with erythropoietic protoporphyria

Abstract

We investigated the molecular defect of the ferrochelatase gene in a Japanese patient with erythropoietic protoporphyria (EPP), and identified a novel 16 base pair (574-589) deletion within exon 5. This deletion resulted in a frame-shift mutation and created a premature stop codon at amino acid position 198. The same molecular defect was also identified in his mother and a brother who had symptomatic EPP, but not in his father who was asymptomatic. The subjects with EPP were homozygous for the low expression haplotype, while his father was heterozygous for this haplotype. These results indicate that the combination of a 16 base pair deletion and low expression of the wild-type allelic variant is responsible for EPP in this pedigree.

Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias

“…Moreover, in all recently studied populations, hitherto unreported mutations continue to emerge. This continuing emergence of novel mutations despite the identification of more than 420 mutations, and the low de novo mutation rate demonstrates the usefulness of preliminary identification of the causative mutations in each newly-diagnosed family so that relatives with latent porphyria can be accurately identified (Donnelly et al 2002;Gregor et al 2002;Wiman et al 2002;Yasui et al 2002). Most mutations were restricted to a single family, and in accordance with the autosomic dominant inheritance, each patient had a single mutation restricted to one allele.…”

Novel mutations and phenotypic effect of the splice site modulator IVS3-48C in nine Swedish families with erythropoietic protoporphyria

“…The IVS3-48T alleles in trans to the mutated allele are associated with different subhaplotypes in the father and his son (287A:921A and 287G:921A, respectively). The 287AϾG transition seen in the son corresponds to the exchange Q96R, and has been shown to result in a slight decrease in FECH activity (91.8% of normal) when expressed in Escherichia coli (Yasui et al 2002). The difference at this position is therefore not likely to account for the difference in phenotype between these two individuals.…”

“…The gene has been mapped to chromosomal position 18q21.3 (Brenner et al 1992;Taketani et al 1992) and contains 11 exons and spans over 45 kb (Taketani et al 1992). Several EPPcoupled mutations have been identified in the FECH gene (Chen et al 2002;Frank et al 1999;Gouya et al 1999;Remenyik et al 1998;Rufenacht et al 2001;Yasui et al 2002;Yotsumoto et al 2001;Human Gene Mutation Database).…”

Molecular characterization of erythropoietic protoporphyria in South Africa

“…The presence of the IVS3‐48C polymorphism in individuals presenting with EPP, and its role in clinical expression of the disease, have been further demonstrated in Swiss, 21 North American, 22–24 Swedish, 25 British, 15 Japanese 26,27 and Israeli patients 28 …”