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

MARCUCCI, VALERIA; COLOMBO, FEDERICO; BATLLE, ALCIRA; PARERA, VICTORIA; ROSSETTI, MARIA VICTORIA

Cardiff

Congreso; International Porphyrins and Porphyrias Meeting; 2011

British Association of Dermatologists

Porphyria cutanea tarda (PCT) is a disorder of haem 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 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 includes possible interactions with a transcriptional complex and epigenetic factors, contributing to the triggering of the disease. We have investigated three 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 (ESE) site] and c.636 + 30G>T [in intron 6 and located in an intronic splicing silencer (ISS) site] and their associations in the expression of PCT in 74 patients with PCT (including hPCT and sPCT). Polymorphism variants were also studied in 62 control volunteers. All flanking sequences of genetic variants were amplified by polymerase chain reaction (PCR) and digested with specific endonucleases, or heminested allele-specific oligonucleotide PCR. The polymorphic variants c.1-263A (0Æ313, 0Æ284 and 0Æ286 in hPCT, sPCT and control volunteers, respectively) and c.603G (0Æ159, 0Æ188 and 0Æ250 in hPCT, sPCT and control volunteers, respectively) of the UROD gene presented no significant differences in the allelic frequencies in the study groups. However, the variant c.636 + 30T presented significant differences between hPCT and control volunteers (allelic frequency 0Æ802 and 0Æ698, respectively; Fisher?s exact test P < 0Æ05). The odds ratio (OR) for the variants c.1-263A and c.603G (1Æ01 and 0Æ64, respectively) indicates that these polymorphic variants are present with equal probability in the study groups. However, homozygous genotypes for the variant c.603G were found only in 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 (2Æ62) indicates that this polymorphic variant is a risk factor for PCT patients. The presence of the variant c.603G on the ESE site makes it more functional than the ancestral variant c.603A, its 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 an ISS site may cause the appearance of alternative transcripts of the UROD gene, this probably being one of the causes of clinical manifestation of the disease.