We describe five new mutations in the
uroporphyrinogen decarboxylase (UROD) gene. All mutations were observed in conjunction with decreased erythrocyte UROD and clinical familial
porphyria cutanea tarda (fPCT), (four families) or
hepatoerythropoietic porphyria (HEP), (one family). The fPCT mutations included three point mutations that resulted in amino acid substitutions: a
lysine to
glutamine at
amino acid position 253 (exon 7); a
glycine to
arginine at position 318 (exon 10); an
isoleucine to
threonine at position 334 (exon 10). The
lysine to
glutamine at
amino acid position 253 was found in conjunction with a single C
nucleotide deletion in exon 8 on the same allele of the UROD gene in the same family. This deletion resulted in a shift in the reading frame and the introduction of a
premature stop codon 8
amino acids downstream. 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 observed in an individual diagnosed with HEP, resulting in an
alanine to
glycine 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 examined using in vitro
protein expression and with activity assessed using pentacarboxylic
acid porphyrinogen I as a substrate for UROD. Although three mutations reduced UROD activity to < 15% of normal, one resulted in a UROD
protein with 50% functional activity and the other had near normal activity. These results indicate that many different genetic lesions of the UROD gene are associated with fPCT.