title: Molecular basis of variegate porphyria: a de novo insertion mutation in the protoporphyrinogen oxidase gene.
abstract: The porphyrias are disorders that result from the inherited or acquired dysregulation of one of the eight enzymes in the heme biosynthetic pathway. Variegate porphyria (VP) is characterized by deficiencies in protoporphyrinogen oxidase (PPO) and has recently been genetically linked (Z = 6.62) to the PPO gene on chromosome 1q21. In this study, we have identified two sequence variants in the PPO gene in a family with VP. The first is a neutral polymorphism at the -47 position of intron 2; this polymorphism is present in the general population and is unlikely to underlie the VP phenotype. The second is a mutation in the PPO gene in a patient with VP; the mutation consists of an apparently de novo 2-bp insertion in exon 3 of PPO and results in a frameshift and downstream premature termination codon. These data establish that a frameshift mutation in PPO is the underlying mutation in this patient with VP and explain the sporadic occurrence of the phenotype in this family.
authors.affiliation: Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lam
authors.forename: L
authors.initials: L
authors.lastname: Dragan
authors.forename: H C
authors.initials: HC
authors.lastname: Tsou
authors.forename: H
authors.initials: H
authors.lastname: Merk
authors.forename: M
authors.initials: M
authors.lastname: Peacocke
authors.forename: G
authors.initials: G
authors.lastname: Goerz
authors.forename: S
authors.initials: S
authors.lastname: Sassa
authors.forename: M
authors.initials: M
authors.lastname: Poh-Fitzpatrick
authors.forename: D R
authors.initials: DR
authors.lastname: Bickers
authors.forename: A M
authors.initials: AM
authors.lastname: Christiano
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D017931:DNA Primers; D004251:DNA Transposable Elements; D005091:Exons; D005260:Female; D005420:Flavoproteins; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009679:Nuclear Family; D010088:Oxidoreductases / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011162:Porphobilinogen / Q000097:blood; D017119:Porphyria Cutanea Tarda / Q000201:enzymology / Q000235:genetics*; D017094:Porphyrias, Hepatic / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D011166:Porphyrins / Q000378:metabolism; D050768:Protoporphyrinogen Oxidase
chemical_list: D017931:DNA Primers; D004251:DNA Transposable Elements; D005420:Flavoproteins; D024101:Mitochondrial Proteins; D011166:Porphyrins; D011162:Porphobilinogen; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C493978:PPOX protein, human; D050768:Protoporphyrinogen Oxidase