Co‐existence of two functional mutations on the same allele of the human ferrochelatase gene in erythropoietic protoporphyria

Abstract

Erythropoietic protoporphyria (EPP) is an autosomal dominant disease with incomplete penetrance due to reduced activity of ferrochelatase (FECH), a mitochondrial enzyme that catalyzes the final step of the heme biosynthetic pathway. The clinical phenotype of EPP results from co-inheritance of a mutated allele and a wild-type low-expressed allele of the FECH gene. To date, more than 88 different mutations have been identified in the FECH gene of patients with EPP. There are evidences suggesting that an entire haplotype (-251G, IVS1-23T and IVS3-48C) reduces allele expression. In this study, we searched for the -251A/G, IVS1-23C/T and IVS3-48T/C polymorphisms in two unrelated Italian families with EPP. In all the patients, carrying the -250G>C mutation in the promoter region, the IVS3-48C on the other allele showed apparent homozygosity and absence of Mendelian segregation. By RNA and long polymerase chain reaction analysis, we identified a deletion of 5576 bp (g12490_18067), including exons 3 and 4, in cis with the -250G>C mutation in the promoter.

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…Thus, in pulmonary arterial hypertension, a disease caused by mutations in the bone morphogenetic protein receptor type 2 ( BMPR2 ) gene, the penetrance of the BMPR2 disease allele is dependent upon the level of expression of the wild-type BMPR2 allele (Hamid et al 2009a). Similarly, in erythropoietic protoporphyria, an autosomal dominant condition caused by mutations in the ferrochelatase ( FECH ) gene, the penetrance of the pathogenic FECH allele is influenced by the level of expression of the wild-type FECH allele (Gouya et al 1999; 2002; Di Pierro et al 2007). Other examples of autosomal dominant conditions where the degree of clinical penetrance is modulated by differential expression of the wild-type and mutant alleles include hereditary elliptocytosis ( SPTA1 , Wilmotte et al 1993), Marfan syndrome ( FBN1 , Hutchinson et al 2003), retinoblastoma ( RB1 , Taylor et al 2007), colorectal cancer ( APC , Yan et al 2002; TGFBR1 , Valle et al 2008) and breast and ovarian cancer ( BRCA1 , Ginolhac et al 2003).…”

Modeling SNP mediated differential targeting of homologous 3′UTR by microRNA

“…In absence of the SNP, an individual with identical mutation in FECH is unaffected. 3,4 The effect of SNP at miRNA target site modulating posttranscriptional regulation has increasingly been reported. 22,23 Such cases could be examined for variations in penetrance of the associated mutations.…”

“…In erythropoietic protoporphyria (EPP), an autosomal dominant disorder of heme biosynthesis, the clinical phenotype results from coinheritance of a mutant allele and a low-expressed wild-type allele of FECH. 3,4 Brugada syndrome, a cardiac disorder, is inherited as an autosomal dominant mutation but shows incomplete penetrance. Poelzing et al reported that individuals carrying a H558R polymorphism in trans, on the normal allele of the gene, in addition to the disease causing R282H mutation in SCN5A are asymptomatic, suggesting that the H558R polymorphism overrides the effect of the mutant allele.…”

Porphyrias at a glance: diagnosis and treatment

“…A wide heterogeneity of genetic defects has been reported although predominant mutations are more frequent than in acute porphyrias. Large deletions are really prevalent in chronic porphyrias mostly in EPP [50][51][52]. Although patients with gene defects causing truncated proteins might be more vulnerable to liver complications [53], no exact genotypephenotype correlation predicting liver damage has been reported.…”