Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles.
Familial porphyria cutanea tarda (f-PCT) results from the half-normal activity of uroporphyrinogen decarboxylase (URO-D). Heterozygotes for this autosomal dominant trait are predisposed to photosensitive cutaneous lesions by various ecogenic factors, including iron overload and alcohol abuse. The 3.6-kb URO-D gene was completely sequenced, and a long-range PCR method was developed to amplify the entire gene for mutation analysis. Four missense mutations (M165R, L195F, N304K, and R332H), a microinsertion (g10insA), a deletion (g645Delta1053), and a novel exonic splicing defect (E314E) were identified. Expression of the L195F, N304K, and R332H polypeptides revealed significant residual activity, whereas reverse transcription-PCR and sequencing demonstrated that the E314E lesion caused abnormal splicing and exon 9 skipping. Haplotyping indicated that three of the four families with the g10insA mutation were unrelated, indicating that these microinsertions resulted from independent mutational events. Screening of nine f-PCT probands revealed that 44% were heterozygous or homozygous for the common hemochromatosis mutations, which suggests that iron overload may predispose to clinical expression. However, there was no clear correlation between f-PCT disease severity and the URO-D and/or hemochromatosis genotypes. These studies doubled the number of known f-PCT mutations, demonstrated that marked genetic heterogeneity underlies f-PCT, and permitted presymptomatic molecular diagnosis and counseling in these families to enable family members to avoid disease-precipitating factors.
Mendez
M
M
Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Sorkin
L
L
Rossetti
M V
MV
Astrin
K H
KH
del C Batlle
A M
AM
Parera
V E
VE
Aizencang
G
G
Desnick
R J
RJ
D000483:Alleles; D019943:Amino Acid Substitution; D001118:Argentina; D001483:Base Sequence; D004251:DNA Transposable Elements; D004795:Enzyme Stability; D005091:Exons; D005799:Genes, Dominant; D006580:Genetic Carrier Screening; D006432:Hemochromatosis / Q000235:genetics*; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D017119:Porphyria Cutanea Tarda / Q000201:enzymology* / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014575:Uroporphyrinogen Decarboxylase / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*
D004251:DNA Transposable Elements; D011994:Recombinant Proteins; D014575:Uroporphyrinogen Decarboxylase