Genetic Analysis of Argentinean Variegate

GRANATA, BARBARA XOANA; MELITO, VIVIANA; BATLLE, ALCIRA; PARERA, VICTORIA; ROSSETTI, MARIA VICTORIA

Lucerna

Congreso; INTERNATIONAL CONGRESS ON PORPHYRINS AND PORPHYRIAS; 2013

Variegate Porphyria (VP) is a disorder of heme biosynthesis that results from a partial deficiency of Protoporphyrinogen Oxidase (PPOX). It is essentially inherited as an autosomal dominant trait, and can present acute, cutaneous or mixed symptoms. At present about 150 different mutations in PPOX gene causing VP have been reported. The aim of this work is to give an overview of the molecular studies conducted at the Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP) in VP Argentinean patients. So far, we have studied 35 unrelated Argentinean families at the molecular level. All the mutations found are restrictive to one or at least two families, except for c.1043insT which is present in 40 % of the families. The majority of the mutations are exonic, except for c.338 + 3 insT and c.808-1 G > C. These last two alterations proved to affect splicing, as two other mutations present in the last (c.807G > A) and first (c.808-1G > C) base of the corresponding exon. 10 % of the mutations described in our country affect splicing. Among the exonic changes, 16 % are deletions and 40 % are insertions. All of them generate a premature stop codon downstream. The 87,5 % of the insertions are c.1043insT. The remaining 34 % of the mutations are missense, all of them known to affect the enzymatic activity. In terms of the symptoms, in the splicing group the main clinical  feature is the mixed one (45 % ). The deletions are mostly associated  with cutaneous symptoms (50 % ). The missense and all of the insertions  have a similar distribution pattern between the three types of symptoms. Dividing the insertion group into c.1043insT and others,  the profile changes: while the most frequent insertion is associated to  a 30 % of cutaneous symptoms, the other insertions are 100 % linked  to acute signs; although the number of patients in this last group is  too small (four) to get a true conclusion about this. In summary, we have a mutation that is strongly present in our  country (c.1043insT). Regarding the association with clinical features,  this mutation is not always accompanied by the same type  of symptom, which reveals that a genotype-phenotype relationship  cannot be established. Nevertheless, it is important to scan the PPOX gene for this  alteration when a VP is suspected, since it is highly represented in our population. About the other mutations, the results are not sufficient to  ascertain a genotype-phenotype correlation.