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

COLOMBO, F; GRANATA, B X; MARTINEZ, J; MARCUCCI, V; MELITO, VA; BATLLE, A; ROSSETTI, MV; PARERA, VE

Cardiff

Congreso; International Porphyrins and Porphyrias Meeting; 2011

British Association of Dermatologists

Combined inheritance of genetic variants in the ferrochelatase gene (FECH) are implicated in the clinical manifestation of erythropoietic protoporphyria (EPP). Genetic variants in the FECH gene include more than 174 mutations and 538 single nucleotide polymorphisms (SNPs). We have investigated mutations and 5 polymorphisms in the FECH gene (c.1-251A>G; c.68-23C>T; c.315-48T>C, c.798G>C and c.921G>A) and their associations in the expression of EPP in 27 EPP patients, belonging to 18 non-consanguineous families and 37 relatives. Polymorphisms variants were also studied in 35 patients with other porphyrias and 110 control volunteers. All flanking sequences of genetic variants were amplified by PCR and automatically sequenced or digested with specific endonucleases. In EPP, only those individuals who inherited a mutant allele combined in trans to a low expression allele c.1-251G, c.68-23T, and c.315-48C, trigger clinical symptoms. The absence of c.315-48C variant was sufficient for not triggering the porphyria. However, in our population, the variants c.1-251A>G, c.68-23C>T and c.315-48T>C showed high levels of cosegregation, observing prevalence of the haplotype formed by the ancestral variants ACT (69.71%) while polymorphic variant GTC was found in only 16.90% of the alleles studied. In EPP asymptomatic carriers also 91.66% of the alleles presented the ACT haplotype in trans to a mutated allele. Relatives without mutation who presented GTC haplotype in homozygous state did not show biochemical or clinical symptoms of the disease. The GTC haplotype showed differences between EPP patients, controls and patients with other porphyrias (allelic frequency 0.500*, 0.169 and 0.025*). However, only c.315-48C variant showed significant differences between healthy volunteers and patients with other porphyrias (0.200 and 0.057* respectively). This GTC haplotype was observed only in 2 VP and 1 PCT patients. These VP patients carried in trans to its mutated allele the wild type c.1-247A, c.1-151G, c.1-128C, and c.88-47G haplotype in PPOX gene. PCT patient had not mutation in the URO-D gene. These patients may admit the failure of one allele of the FECH gene.   In the autosomal dominant inheritance form of EPP, the variant c.315-48C in trans to the mutated allele of the FECH gene is sufficient to trigger the disease. The presence of the GTC haplotype in all Argentinean patients with this type of inheritance could be due to the high level of cosegregation of the variant c.315-48C with the c.1-251G and c.68-23T variants in our population. * Fisher´s exact test: P<0.0017, (95% CI)