NEW MUTATIONS IN THE UROPORPHYRINOGEN DECARBOXYLASE GENE IDENTIFIED IN FAMILIES WITH CUTANEOUS PORPHYRIA

We describe five new mutations in the uroporphyrinogen decarboxylase ( UROD) gene. All mutations were observed in conjunction with decreased erythrocyte UROD and clinical familiar porphyria cutanea tarda (fPCT), (four families) or hepatoerythropoietic porphyria (HEP), (one family) . The fPCT mutations included three point mutations that resulted in a mino acid substitutions: a lysine to glutamine at amino acid position 253 (exon 7); a glycine to arginine at position 318 (exon 10): an isol eucine to threonine at position 334 (exon 10). The lysine to glutamine at amino acid position 253 was found in conjunction with a single C n ucleotide deletion in exon 8 on the same allele of the UROD gene in th e same family. This deletion resulted in a shift in the reading frame and the introduction of a premature stop codon 8 amino acids downstrea m. In the fourth family, a 31-bp deletion (nucleotides 828-858: exon 8 ) of the coding region, resulted in a frameshift and the introduction of a stop codon 19 amino acids downstream. A point mutation was observ ed in an individual diagnosed with HEP, resulting in an alanine to gly cine change at amino acid position 80 and was present on both alleles. All mutations were confirmed in at least one other family member. The impact of these mutations on the function of the UROD protein was exa mined using in vitro protein expression and with activity assessed usi ng penta-carboxylic acid porphyrinogen I as a substrate for UROD, Alth ough three mutations reduced UROD activity to <15% of normal, one resu lted in a UROD protein with 50% functional activity and the other had near normal activity, These results indicate that many different genet ic lesions of the UROD gene are associated with fPCT. (C) 1996 by The American Society of Hematology.