title: Molecular basis of variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene.
abstract: Variegate porphyria (VP) is an autosomal dominant disorder characterised by a partial defect in the activity of protoporphyrinogen oxidase (PPO), and has recently been genetically linked to the PPO gene on chromosome 1q22-23 (Z=6.62). In this study, we identified a mutation in the PPO gene in a patient with VP and two unaffected family members. The mutation consisted of a previously unreported T to C transition in exon 13 of the PPO gene, resulting in the substitution of a polar serine by a non-polar proline (S450P). This serine residue is evolutionarily highly conserved in man, mouse, and Bacillus subtilis, attesting to the importance of this residue. Interestingly, the gene for Gardner's syndrome (FAP) also segregates in this family, independently of the VP mutation. Gardner's syndrome or familial adenomatous polyposis (FAP) is also an autosomal dominantly inherited genodermatosis, and typically presents with colorectal cancer in early adult life secondary to extensive adenomatous polyps of the colon. The specific gene on chromosome 5 that is the site of the mutation in this disorder is known as APC (adenomatous polyposis coli), and the gene has been genetically linked to the region of 5q22.
authors.affiliation: Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: J
authors.initials: J
authors.lastname: Frank
authors.forename: H
authors.initials: H
authors.lastname: Lam
authors.forename: E
authors.initials: E
authors.lastname: Zaider
authors.forename: M
authors.initials: M
authors.lastname: Poh-Fitzpatrick
authors.forename: A M
authors.initials: AM
authors.lastname: Christiano
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D004252:DNA Mutational Analysis; D005260:Female; D005420:Flavoproteins; D005736:Gardner Syndrome / Q000235:genetics; D017491:Genes, APC; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010375:Pedigree; D017094:Porphyrias, Hepatic / Q000235:genetics* / Q000503:physiopathology; D050768:Protoporphyrinogen Oxidase; D016415:Sequence Alignment
chemical_list: D005420:Flavoproteins; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C493978:PPOX protein, human; C493979:Ppox protein, mouse; D050768:Protoporphyrinogen Oxidase