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

Hum Genet. 2004 Feb;114(3):256-62. doi: 10.1007/s00439-003-1059-5. Epub 2003 Dec 11.


We have recently demonstrated that in an autosomal dominant porphyria, erythropoietic protoporphyria (EPP), the coinheritance of a ferrochelatase (FECH) gene defect and of a wild-type low-expressed FECH allele is generally involved in the clinical expression of EPP. This mechanism may provide a model for phenotype modulation by minor variations in the expression of the wild-type allele in the other three autosomal dominant porphyrias that exhibit incomplete penetrance: acute intermittent porphyria (AIP), variegata porphyria (VP) and hereditary coproporphyria (HC), which are caused by partial deficiencies of hydroxy-methyl bilane synthase (HMBS), protoporphyrinogen oxidase (PPOX) and coproporphyrinogen oxidase (CPO), respectively. Given the dominant mode of inheritance of EPP, VP, AIP and HC, we first confirmed that the 200 overtly porphyric subjects (55 EPP, 58 AIP, 56 VP; 31 HC) presented a single mutation restricted to one allele (20 novel mutations and 162 known mutations). We then analysed the available single-nucleotide polymorphisms (SNPs) present at high frequencies in the general population and spreading throughout the FECH, HMBS, PPOX and the CPO genes in four case-control association studies. Finally, we explored the functional consequences of polymorphisms on the abundance of wild-type RNA, and used relative allelic mRNA determinations to find out whether low-expressed HMBS, PPOX and the CPO alleles occur in the general population. We confirm that the wild-type low-expressed allele phenomenon is usually operative in the mechanism of variable penetrance in EPP, but conclude that this is not the case in AIP and VP. For HC, the CPO mRNA determinations strongly suggest that normal CPO alleles with low-expression are present, but whether this low-expression of the wild-type allele could modulate the penetrance of a CPO gene defect in HC families remains to be ascertained.

MeSH terms

  • Acute Disease
  • Alleles*
  • Case-Control Studies
  • Cohort Studies
  • Coproporphyrinogen Oxidase / genetics
  • DNA Mutational Analysis
  • Ferrochelatase / genetics
  • Flavoproteins
  • Genes, Dominant*
  • Humans
  • Hydroxymethylbilane Synthase / genetics
  • Mitochondrial Proteins
  • Mutation
  • Oxidoreductases Acting on CH-CH Group Donors / genetics
  • Penetrance*
  • Polymorphism, Single Nucleotide
  • Porphyria, Hepatoerythropoietic / diagnosis
  • Porphyria, Hepatoerythropoietic / genetics*
  • Porphyrias, Hepatic / diagnosis
  • Porphyrias, Hepatic / genetics*
  • Protoporphyrinogen Oxidase
  • RNA, Messenger / analysis
  • Reproducibility of Results
  • White People / genetics


  • Flavoproteins
  • Mitochondrial Proteins
  • RNA, Messenger
  • Oxidoreductases Acting on CH-CH Group Donors
  • Coproporphyrinogen Oxidase
  • PPOX protein, human
  • Protoporphyrinogen Oxidase
  • Hydroxymethylbilane Synthase
  • Ferrochelatase