MOLECULAR HETEROGENEITY OF PORPHYRIA CUTANEA TARDA IN SPAIN: IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF MUTATIONS IN THE UROPORPHYRINOGEN DECARBOXYLASE GENE

*Manuel Mendez1, *Pamela Poblete-Gutiérrez2, Jaime Cruz-Rojo 1, María García-Bravo1 María-Concepción Garrido1, Rafael Enríquez de Salamanca1, Jorge Frank2, Antonio Fontanellas1

*These authors contributed equally to this study. 1Centro de Investigación. Hospital 12 de Octubre, Madrid, Spain 2Department of Dermatology and Allergology and Porphyria Center, University Clinic of the RWTH Aachen, Aachen, Germany

Porphyria cutanea tarda (PCT) is resulting from decreased activity of hepatic uroporphyrinogen decarboxylase (UROD). We investigated the molecular basis of PCT by screening the UROD DNAs of 71 unrelated Spanish patients with PCT, using polymerase chain reaction, heteroduplex analysis, automated sequencing, and restriction enzyme digestion.

Ten novel and 4 previously described mutations (of which, two of them were detected in Spanish patients) were identified in 15 patients (21%). The probability of each novel missense mutation in decreasing UROD activity was assessed by prokaryotic expression studies. Other 52 patients (73%) showed no mutation or polymorphism and were classified as sporadic-PCT. Four patients (6%) exhibiting normal erythrocyte UROD activity with family history of the disease were classified as Type III-PCT. No mutation was found in the UROD gene from Type III-patients, and confirms that inherited factors other than mutations in the UROD gene, may predispose to PCT.

Our results indicate that the frequency of familial-PCT in Spain is 21%. Among the 14 molecular defects observed in our patients, 12 of them seem to be restricted to the Spanish population and confirm the molecular heterogeneity in familial-PCT.