Mutations in familial porphyria cutanea tarda: Two novel and two previously described for hepatoerythropoietic porphyria

Uroporphyrinogen decarboxylase (URO-D) deficiency is responsible for two forms of genetic cutaneous porphyria: familial porphyria cutanea tarda (f-PCT) and hepatoerythropoietic porphyria (HEP). The f-PCT transmitted as an autosomal dominant trait, is characterized by photosensitive cutaneous lesions frequently associated to hepatic dysfunction and is precipitated by various ecogenic factors. The HEP, transmitted as a recessive trait, is more severe than f-PCT and would be considered as the homozygous form of f-PCT. For the mutational analysis of f-PCT patients, the entire URO-D gene was amplified and each exon, intron-exon boundaries and the promoter region were cycle sequenced. Five mutations were found in 6 unrelated families studied, of these, two were new: a nonsense mutation in exon 6 (W159X) and a splice defect in intron 9 (IVS9(-1)G-->C). The other two missense mutations, P62L and A80G, had been previously reported in the homozygous state in HEP families. The g10insA, reported in our laboratory, was again identified in other two unrelated families. In addition 3 novel URO-D polymorphisms in non-coding regions were found. The reverse transcription-PCR and sequencing of the splice mutation carrier's RNA did not reveal the presence of an abnormal mRNA, suggesting that no stable transcript from the mutated allele is synthesized. These results increase to 39 the number of mutations identified in the URO-D gene; 4 of them causing both HEP and f-PCT.