Laurent Gouya, Caroline Martin-Schmitt, Anne-Marie Robreau, Saïd Lyoumi, Vasco Da Silva, Hervé Puy, Jean-Charles Deybach*
Centre Français des Porphyries, INSERM-Faculté X. Bichat, Hôpital Louis Mourier, Colombes, France
Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis resulting from partial deficiency of ferrochelatase (FECH) and characterized by early onset of lifelong acute photosensitivity. Individuals who are heterozygous for a FECH mutation are asymptomatic, despite having half-normal FECH activity. Recently, we have shown that the inheritance of the common SNP IVS3-48C allele trans to the mutation appears to explain photosensitivity in most EPP patients. Then, FECH activity is reduced below a critical threshold of about 35% of normal. We evaluate the contribution to the occurrence of photosensitivity of the IVS3-48C allele compared to alternative mechanisms in the 113 unrelated French Caucasian EPP families. We also studied the frequency of IVS3-48C allele in 347 unrelated healthy subjects from 4 ethnically diverse human populations and examined whether this allelic frequency may influence the prevalence of clinical EPP in a specific population. Haplotypes analysis of alleles carrying the IVS3-48C allele was performed, the phylogenic origin of these haplotypes was determined and the level of functional constraint of the FECH gene was estimated. In the EPP cohort, the autosomal dominant disease with co-inheritance of the IVS3-48C allele is the usual explanation for overt EPP in 95 % of the cases (95 % confidence interval: 93 to 98). The IVS3-48C allele is not involved in 6 families: autosomal recessive disease is found in 4 families, the co-inheritance of a deleterious mutation and a mild Y191H mutation is found in one family, and partial hepatectomy is a co-precipitating factor in one overt EPP patient. The frequency of the IVS3-48C allele widely differs between East Asian (35%), European Caucasian (11%), North African (2.3%), and West African (<1%) populations. EPP prevalence strongly correlates to IVS3-48C allele frequency in Caucasian population. This IVS3-48C allele frequency should be related to most EPP cases reported in Asia and could explain the absence of EPP patients reported so far in black Afrikaners. Haplotypes analysis based on 12 polymorphic loci identified five common haplotypes closely linked altogether. The phylogenic origin of these haplotypes strongly suggest that the IVS3-48C allele originates from a recent single mutational event. The alignment of orthologous FECH sequences between human and P. troglodytes chimpanzee indicates that FECH gene is under strong negative functional constraint. Altogether these results improve the risk prediction and genetic counselling in EPP families and shed new light on genetic predisposition to a Mendelian disorder which depends on the frequency of a single common polymorphism in the population under study.