Functional associations of genetic variants involved in the clinical manifestation of erythropoietic protoporphyria in the Argentinean population

Background Combined inheritance of genetic variants in ferrochelatase gene (FECH) are implicated in clinical manifestation of Erythropoietic Protoporphyria (EPP). Objective Identify the genetic variants in FECH gene and their associations in the expression of EPP in Argentina. Determine the allelic frequency of polymorphic variants, associations in cis and its linkage disequilibrium. Methods The FECH gene was PCR‐amplified and sequenced. Allelic variants of intragenic polymorphisms were identified by PCR followed by sequencing or restriction digestion analysis. Residual FECH activity was determined by prokaryotic expression in Escherichia coli JM109. Data were analyzed using Haploview and Statistix 9. Results Ten mutations were identified: three novel (p.S222N; p.R298X and p.R367X) and seven already known (g.12490_18067del; p.R115X; p.I186T; c.580_584delTACAG; c.598 + 1 G>T; p.Y209X and p.W310X). The p.R115X mutation was found in two families. The p.S222N mutation expressed 5% of normal activity. Only individuals who inherited a mutation combined in trans to a low expression allele c.1‐251G, c.68‐23T, and c.315‐48C, showed clinical symptoms. The absence of c.315‐48C variant was sufficient for not triggering EPP. However, these variants showed high levels of cosegregation and GTC haplotype is over‐represented in EPP patients. Conclusion In the dominant inheritance form of EPP, c.315‐48C variant in trans to the mutated allele is sufficient to trigger the disease. The presence of GTC haplotype in all patients with dominant EPP could be due to the high level of cosegregation of c.315‐48C with c.1‐251G and c.68‐23T variants in our population.