CONICET | Buscador de Institutos y Recursos Humanos

Porphyria cutanea tarda (PCT), the most common porphyria, is caused by decrease activity of uroporphyrinogen decarboxylase (UROD) in the liver. This cytosolic enzyme catalyzes the fifth step in the heme biosynthetic pathway, the sequential decarboxylation of uroporphyrinogen to coproporphyrinogen. The disease usually occurs in adulthood and is characterized by cutaneous photosensitivity, hyperpigmentation, skin fragility and hypertrichosis, due to by the overproduction of uroporphyrinogen and other highly carboxylated porphyrinogens as result of the enzyme deficiency. PCT is generally sporadic, but in about 20-30% of cases the disease is transmited as an autosomal dominant trait. This form of the disease is called familial PCT (F-PCT) and patients have about 50% reduced UROD activity in all tissues due to heterozygosity of mutations in the UROD gene. In the present study we have characterized the molecular defect of seventeen unrelated Argentinean patients with F-PCT. We have identified eleven mutations in the UROD gen, four novel and seven previously described. The novel mutations were: a microinsertion at the 5? splice junction of intron 2, the deletion of valine 90, a 22 bp deletion in exon 6 and a microdeletion in part of the polyadenylation signal. The consequences of the splice site insertion were assessed by RT-PCR and sequencing, whereas functional characterization of the aminoacid deletion was made by prokaryotic expression studies. Mutations g10insA and M165R, previously found in Argentinean patients, were recurrently identified among these patients, representing altogether 40% of the mutant alleles characterized to date, which are the more prevalent in Argentina