HETEROGENEITY OF MUTATIONS AND GTC HAPLOTYPE ASSOCIATED WITH ERYTHOPOIETIC PROTOPORPHYRIA IN ARGENTINA

COLOMBO FP; MARTINEZ JE; ROSSETTI MV; BATLLE A; PARERA VE

Estocolmo - Suecia

Congreso; BERZELIUS SYMPOSIUM -Porphyrins and Porphyrias 2009- Stockholm, Sweden; 2009

The Swedish Society of Medicine

Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by partial deficiency of ferrochelatase (FECH). Its Inheritance is complex and can be either autosomal dominant with low clinical penetrance, or autosomal recessive. The clinical phenotype of EPP results from co-inheritance of a mutated allele and a wild-type low-expressed allele of the FECH gene. More than 85 mutations and 285 polymorphisms (SNPs) in the FECH gene have been identified.   We analyzed FECH gene mutations in  24 Argentinean EPP patients from 17 non-consanguineous families belonging to 35 biochemically diagnosed EPP families. We also studied four intragenic  polymorphisms:-251 A/G; IVS1-23C/T; IVS3-48T/C and c798 G/C in these patients, their relatives and in 100 healthy volunteers All exons and flanking sequence of intragenic polymorphism of  the FECH gene were PCR amplified and sequenced or digested with  specific restriction enzyme respectively. In 13 families we detected 14 mutations responsibles of EPP. Only one mutation, R115X, was found in 2 families.  Predominant type of mutations are single-nucleotide substitutions in the coding region of the FECH gene (50%), with the highest prevalence of nonsense mutations (28,57%). Prevalence of the dominant and recessive autosomal forms of EPP is 92,7%  and 7,7%, respectively. There were three cases with fatal liver failure, one of whom presented an autosomal recessive inheritance. Comparing the results for the different SNPs detected, there were significantive differences between the patients and controls in 3 of 4 SNPs, except the 798 G/C SNP. One of the patients have  not inherited the entire GTC haplotype (-251G, IVS1–23T and IVS3–48C), he carried  ATC haplotype associated in trans to a mutated allele. We determined the heterogeneity of mutations in the FECH gene and the higher incidence of certain nonsense mutations in our population. Complex  genotype-phenotype relationships in EPP may be due to accumulation of SNPs in cis of  diverse functionality  in the FECH gene, modulating in trans the clinical  expression of the disease. It is of note that the presence of variations in the genomic sequence, allow us to predict the development of the disease in their relatives and in future the severity of the manifestation.