Contribution of a Common Single-Nucleotide Polymorphism to the Genetic Predisposition for Erythropoietic Protoporphyria

Abstract

Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis that results from a partial deficiency of ferrochelatase (FECH). Recently, we have shown that the inheritance of the common hypomorphic IVS3-48C allele trans to a deleterious mutation reduces FECH activity to below a critical threshold and accounts for the photosensitivity seen in patients. Rare cases of autosomal recessive inheritance have been reported. We studied a cohort of 173 white French EPP families and a group of 360 unrelated healthy subjects from four ethnic groups. The prevalences of the recessive and dominant autosomal forms of EPP are 4% (95% confidence interval 1-8) and 95% (95% confidence interval 91-99), respectively. In 97.9% of dominant cases, an IVS3-48C allele is co-inherited with the deleterious mutation. The frequency of the IVS3-48C allele differs widely in the Japanese (43%), southeast Asian (31%), white French (11%), North African (2.7%), and black West African (<1%) populations. These differences can be related to the prevalence of EPP in these populations and could account for the absence of EPP in black subjects. The phylogenic origin of the IVS3-48C haplotypes strongly suggests that the IVS3-48C allele arose from a single recent mutational event. Estimation of the age of the IVS3-48C allele from haplotype data in white and Asian populations yields an estimated age three to four times younger in the Japanese than in the white population, and this difference may be attributable either to differing demographic histories or to positive selection for the IVS3-48C allele in the Asian population. Finally, by calculating the KA/KS ratio in humans and chimpanzees, we show that the FECH protein sequence is subject to strong negative pressure. Overall, EPP looks like a Mendelian disorder, in which the prevalence of overt disease depends mainly on the frequency of a single common single-nucleotide polymorphism resulting from a unique mutational event that occurred 60,000 years ago.

The porphyrias: advances in diagnosis and treatment

“…To date, Ͼ 135 FECH loss-offunction mutations have been identified, including a common low expression allele (IVS3-48T Ͼ C), which is present in ϳ 10% of European whites with various frequencies in other ethnic/racial groups. 41 Many loss-of-function mutations result in an unstable or absent enzyme protein. The common IVS3-48T Ͼ C splicing mutation results in ϳ 25% normal FECH transcripts.…”

“…In ϳ 5%-10% of EPP families, 2 FECH loss-of-function mutations have been found. 25,41,42 These patients may have a variant EPP phenotype with palmar keratosis. 38 The 2 exon 11 ALAS2 mutations that cause XLP alter the carboxyl-terminal amino acid sequence and result in increased ALAS2 activity and the accumulation of free and zincprotoporphyrins.…”

Iron refractory iron deficiency anemia

“…In animal models, haploinsufficiency of Tmprss6 confers susceptibility to iron deficiency. 58,59 The association between a deleterious mutation and a low expressed allele has been found in several inherited disorders such as erythropoietic protoporphyria, 60 spherocytosis 61 or microcytic anemia due to STEAP3 mutations. 62 This might be a rather frequent situation since recent reports have demonstrated that preferential/specific allele expression may concern 5-20% of the genes.…”

Identification of FECH gene multiple variations in two Chinese patients with erythropoietic protoporphyria and a review

“…As a result, the activity of FECH is reduced or abolished, and the insertion of ferrous iron into protoporphyrin IX to generate heme is impeded. Then excessive protoporphyrin IX accumulates in erythrocytes and other tissues like liver and skin (Gouya et al, 2006). EPP is rare, with the incidence ranging from 1/200 000 to 1/75 000 worldwide (Casanova-Gonzalez et al, 2010).…”