CONICET | Buscador de Institutos y Recursos Humanos

Variegate Porphyria (VP) is a low-penetrance disorder of heme biosynthesis that results from a partial deficiency of Protoporphyrinogen oxidase (PPOX). It is essentially inherited as an autosomal dominant trait; however some cases of double heterozygous and true homozygous have been described. At present about 130 different mutations in PPOX gene causing VP have been reported. We have already studied 12 unrelated Argentinean families at the molecular level and 8 different mutations were found. Sequencing studies carried out in 14 new unrelated Argentinean families identified 10 different mutations, 6 new and 4 previously described. Seven intronic sequence changes (25delA, 1284delA, 1289inC, 1294A>C, 1326delG, 2833insG and 2854delA) were also observed. Three new missense mutations (E34V, G332A and W224G) and 2 novel small deletions (c.133delT, c.925delA) were found. In one family another new frameshift mutation, d.1745insT near the donor splice site for intron 4 was found and so, it is likely to affect its splicing (IVS+3insT). In 9 other families mutations already reported were found: c.1043insT, c.1082insC, A433P and G232R. All mutations were unique to individual families except for E34V mutation which was detected in 2 unrelated families and 1043insT which was found in 5 new apparently unrelated Argentinean families. So, 37% (10/27) Argentinean families carry this mutation indicating that it is the more frequent in the Argentinean population. SNP´s analysis carried out in these families would suggest that they are actually unrelated and so the high occurrence of this small insertion would not seem to be due to a founder effect. This hypothesis is reinforced by the fact that also a thimine insertion two bases downstream (1042/1043insT) was recently found for Swiss patients, indicating that this part of the PPOX gene would be a hot-spot for mutations. Haplotype analysis should still be completed.