RISK EVALUATION OF GENETIC VARIANTS IN THE UROD GENE IN PATIENTS WHIT PORPHYRIA CUTANEA TARDA IN ARGENTINA.

MARCUCCI V; COLOMBO FP; BATLLE A; PARERA VE; ROSSETTI MV

Cardiff

Congreso; Porphyrins and Porphyrias 2011; 2011

British Association of Dermatologists

Porphyria cutanea tarda (PCT) is a disorder of heme biosynthesis caused by partial deficiency of uroporphyrinogen decarboxylase (UROD). There are two main types: sporadic (sPCT) and hereditary (hPCT) forms, generally clinically indistinguishable. The hPCT is transmitted as an autosomal dominant trait with an incomplete penetrance. The clinical expression of PCT is triggered by environmetal factors such as iron overload, hepatotoxic drugs, hormones and alcohol abuse. Genetic variants in the UROD gene include more than 108 mutations and 61 single nucleotide polymorphisms (SNPs). The functionality of these SNPs include possible interactions with a transcriptional complex and epigenetic factors, contributing to the triggering of the disease. We have investigated 3 polymorphisms in the UROD gene: c.1-263T>A (in the promoter region); c.603A>G (in the coding region and located in an Exonic Splicing Enhancer site) and c.636+30G>T (in intron 6 and located in an Intronic Splicing Silencer site) and their associations in the expression of PCT in 74 PCT patients (including hPCT and sPCT). Polymorphisms variants were also studied in 62 control volunteers.  All flanking sequences of genetic variants were amplified by PCR and digested with specific endonucleases or HemiNested ASO-PCR. The polymorphic variants c.1-263A (0.313, 0.284 and 0.286 in hPCT, sPCT and control volunteers respectively) and c.603G (0.159, 0.188 and 0.250 in hPCT, sPCT and control volunteers respectively) of UROD gene, presented no significant differences in the allelic frequencies in the study groups. However, the variant c.636+30T present significant differences between hPCT and control volunteers (allelic frequency 0,802 and 0,698 respectively)*. The Odd Ratio (OR) for the variants c.1-263A and c.603G (1.01 and 0.64 respectively), indicates that theses polymorphic variants are presented with equal probability in the study groups. However, homozygous genotypes for the variant c.603G were only found in the sPCT. This genetic variant c.603A>G is located on an ESE site and this polymorphic variant increases the functionality of this site. The OR for the intronic variant c.636+30T (2.62) indicates that this polymorphic variant is a risk factor for PCT patients. The presence of the variant c.603 G on the ESE site makes it more functional than the ancestral variant c.603A and mRNA resulting in a more stable and therefore more active protein. The biochemical data are consistent with these results. On the other hand, the high prevalence of variant c.636+30T in the PCT patients may be because, being in an ISS site cause the appearance of alternative transcripts of UROD gene, probable being this one of the causes of clinical manifestation of the disease. * Fisher´s exact test: P<0.05, (95% CI)