Familial Porphyria Cutanea Tarda: Characterization of Seven Novel Uroporphyrinogen Decarboxylase Mutations and Frequency of Common Hemochromatosis Alleles

• Published in: American journal of human genetics Vol. 63; no. 5; pp. 1363 - 1375
• Main Authors: Mendez, Manuel, Sorkin, Lonnie, Rossetti, Maria Victoria, Astrin, Kenneth H., Batlle, Alcira M. del C., Parera, Victoria E., Aizencang, Gerardo, Desnick, Robert J.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.11.1998; University of Chicago Press
• Subjects: Alleles; Amino Acid Substitution; Argentina; Base Sequence; Biological and medical sciences; DNA Transposable Elements; Enzyme Stability; Exons; Genes, Dominant; Genetic Carrier Screening; Hemochromatosis; Hemochromatosis - genetics; Humans; Introns; Long-range PCR; Medical sciences; Metabolic diseases; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Mutation, Missense; Mutations; Other metabolic disorders; Pigments (porphyrias, hyperbilirubinemias...); Polymerase Chain Reaction; Porphyria cutanea tarda; Porphyria Cutanea Tarda - enzymology; Porphyria Cutanea Tarda - genetics; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Reverse Transcriptase Polymerase Chain Reaction; Sequence Deletion; Uroporphyrinogen decarboxylase; Uroporphyrinogen Decarboxylase - biosynthesis; Uroporphyrinogen Decarboxylase - chemistry; Uroporphyrinogen Decarboxylase - genetics; Mutations; Hemochromatosis; Porphyria cutanea tarda; Uroporphyrinogen decarboxylase; Long-range PCR; Bullous dermatosis; Porphyria; Skin disease; Pathogenesis; Lyases; Iron; Enzymopathy; Genetic determinism; Heterogeneity; Enzymatic activity; Gene; Carboxy-lyases; Pigments; Haplotype; Human; Photosensitivity; Late; Enzyme; Family study; Metabolic diseases; Exploration; Genotype; Genetic disease; Carbon-carbon lyases; Concomitant disease; Phenotype; Genetic counseling; Risk factor; Skin; Mutation
• DOI: 10.1086/302119
• ISSN: 0002-9297

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 (g645Δ1053), 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.